Roberta Brinton

Interests

Research

My research has focused broadly on the mechanisms by which the aging brain develops late onset Alzheimer’s disease. I lead two large programs of research that are organized under two major themes; 1) Estrogen systems neurobiology and Aging Female Brain and 2) Allopregnanolone regenerative systems neurobiology and regenerative therapeutic for Alzheimer’s disease.

Courses

Scholarly Contributions

Books

• Yin, F., Yin, F., Yao, J., Yin, F., Yao, J., Cadenas, E., Cadenas, E., Brinton, R. D., & Brinton, R. D. (2017). The Metabolic-Inflammatory Axis in Brain Aging and Neurodegeneration. Frontiers Media SA. doi:10.3389/978-2-88945-253-8
• Hogervorst, E., Henderson, V. W., Gibbs, R. B., & Brinton, R. D. (2009). Hormones, Cognition and Dementia : State of the Art and Emergent Therapeutic Strategies - Title Page. Cambridge University Press. doi:10.1017/CBO9780511635700
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• Hogervorst, E., Henderson, V., Gibbs, R., & Brinton, R. (2009). Hormones, Cognition and Dementia: State of the art and emergent therapeutic strategies. Cambridge University Press. doi:10.1017/CBO9780511635700
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  A decade ago, oestrogen-containing hormone therapy was viewed as a promising strategy for the prevention and treatment of dementia and age-related cognitive decline. However, treatment trials in women with Alzheimer's disease showed that oestrogens did not reverse cognitive impairment, and clinical trials in healthy older women indicated that oestrogens did not prevent cognitive decline. The Women's Health Initiative Memory Study trial even suggested an increased risk of dementia with treatment late in life. What happened? How are we to understand these findings? What are the implications for middle-aged and older women? What about testosterone, and what about men? And where do we go from here? This book brings together world-renowned experts in basic and clinical research on sex steroids, aging, and cognition to integrate existing findings with emerging new data, and offer challenging hypotheses on these key issues.

Chapters

• Hernandez, G. D., & Brinton, R. D. (2019). Allopregnanolone as a Therapeutic to Regenerate the Degenerated Brain. In Sex Steroids' Effects on Brain, Heart and Vessels. Springer, Cham. doi:10.1007/978-3-030-11355-1_7
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  Neurosteroids regulate both regeneration and repair systems in the brain. Among this class of molecules, allopregnanolone (Allo) is the first regenerative therapeutic that has been extensively investigated in animal models and more recently in humans for its capacity to promote regeneration in the central and peripheral nervous system. In preclinical analyses, Allo induced generation and survival of new neurons in the hippocampus of aged mice and in transgenic mouse models of Alzheimer’s disease (AD), which was associated with restoration of learning and memory function. Allo is a proliferative factor for both neural stem cells and pre-progenitor oligodendrocytes, increasing both the number of newly generated cells and their survival. Safety characteristics of Allo regulation of neurogenesis indicate that the regenerative system it affects is tightly regulated with closely guarded thresholds for both activation and magnitude of proliferation. In the brain of mice with AD, Allo increased liver X receptor and pregnane X receptor expression, reduced s-amyloid and microglial activation, and increased markers of white matter generation. Results of preclinical studies indicate that an optimal treatment regimen of Allo to promote endogenous regeneration is one that is administered once per week over the course of several months. Allo dose and frequency of exposure are determining factors regulating its therapeutic efficacy. Previous and current human safety exposure data supported by extensive preclinical efficacy data are strong foundations for the clinical development of Allo as a therapeutic to regenerate the degenerated brain.
• Hernandez, G. D., & Brinton, R. D. (2019). The Neurological and Immunological Transitions of the Perimenopause: Implications for Postmenopausal Neurodegenerative Disease. In Sex Steroids' Effects on Brain, Heart and Vessels(pp P9-25). Springer, Cham. doi:10.1007/978-3-030-11355-1_2
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  While the clinical definition of perimenopause focuses on functional changes in the reproductive system, the symptoms of perimenopause are largely neurological and immunological in nature and are observed in women globally across cultures, races, and ethnicities. Estrogen is the master regulator of the metabolic system of the female brain and body. During the perimenopausal transition, what is known as the “estrogen receptor network” is disconnected from the bioenergetic system resulting in a hypometabolic state that is associated with neurological dysfunction, which in some women may increase risk for neurodegenerative disease. Moreover, an APOE4 genotype exacerbates that bioenergetic crisis. Neurological symptoms that emerge during the perimenopause reflect the disruption in multiple estrogen-regulated systems including thermoregulation, sleep and circadian rhythms, sensory processing, affect, and multiple domains of cognitive function. Many of these symptoms are also associated with risk of Alzheimer’s disease (AD), which in women is twice as high than in men. Such elevated risk is correlated to obesity and systemic inflammation due to estrogen depletion occurring in perimenopause and menopause. Aging and neurodegenerative brains are found to be associated with chronic neuroinflammation primarily due to a dysregulation of the innate immunity, mainly driven by senescent microglia. Identifying women with metabolic or inflammatory at-risk phenotypes for late-onset AD might translate into a target population that is likely to respond to estrogen replacement therapy and adjuvant therapies that serve as metabolic regulators. Transitions of female aging involve a set of sequential, system-level adaptations. The perimenopausal transition is a critical period in the neuro-adaptive landscape of the aging brain and represents a window of opportunity for precision hormone therapeutics.
• Brinton, R. D. (2017). 5.19 – Reproductive Aging of Neuroendocrine Systems. In Hormones, Brain and Behavior (Third Edition)(pp 465-476). Science Direct: Elsevier. doi:10.1016/B978-0-12-803592-4.00112-7
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  The neural transition of perimenopause is a midlife transition state in the female that occurs in the context of a fully functioning neurological system and results in reproductive senescence. While viewed as a reproductive transition, the symptoms of the perimenopause are largely neurological in nature. Neurological symptoms that emerge during the perimenopause are indicative of disruption in multiple estrogen-regulated systems including thermoregulation, sleep and circadian rhythms, sensory processing, affect and multiple domains of cognitive function. Through the estrogen receptor (ER) network, estrogen functions as a master regulator to ensure that the brain effectively responds at rapid, intermediate, and long time scales to coordinate signaling and transcriptional pathways that regulate energy metabolism in brain. The ER network becomes uncoupled from the bioenergetic system during the perimenopausal transition and, as a corollary, a hypometabolic state associated with neurological dysfunction emerges. For some women this may increase risk for late-life neurodegenerative disease. Conversely, the perimenopause represents a window of opportunity to prevent age-related neurological disease. This chapter considers the significance of perimenopausal neurological symptoms, their relationship to the estrogenic receptor network control of brain metabolism, and the parallels between the perimenopause and transition state dynamics. Further, gaps in mechanistic and clinical understanding of the perimenopause are considered. The perimenopause fulfills criteria for a ‘critical period’ in the neuroadaptive landscape of aging in the female brain. For some, this critical transition period can be a tipping point for the emergence of neurological disease in later life.
• Yao, J., & Brinton, R. (2012). Estrogen Regulation of Mitochondrial Bioenergetics. Implications for Prevention of Alzheimer's Disease. In Current State of Alzheimer's Disease Research and Therapeutics(pp 327-371). Elsevier. doi:10.1016/B978-0-12-394816-8.00010-6
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  Alzheimer's disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid. Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance. Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The "healthy cell bias of estrogen action" hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy. © 2012 Elsevier Inc.
• Liu, L., Liu, L., & Brinton, R. D. (2011). Gonadal Hormones, Neurosteroids, and Clinical Progestins as Neurogenic Regenerative Agents: Therapeutic Implications. In Hormones in Neurodegeneration, Neuroprotection, and Neurogensis. Wiley‐VCH Verlag GmbH & Co. KGaA. doi:10.1002/9783527633968.CH17
• Brinton, R. (2010). Neuroendocrinology of Aging. In Geriatrics and Clinical Gerontology(pp 163-169). Saunders Elsevier. doi:10.1016/B978-1-4160-6231-8.10027-3
• Henderson, V., & Brinton, R. (2010). Menopause and Mitochondria: Windows into Estrogen Effects on Alzheimerȁ9;s Disease Risk and Therapy. In Neuroendocrinology Pathological Situations and Diseases. Elsevier. doi:10.1016/S0079-6123(10)82003-5
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  Metabolic derangements and oxidative stress are early events in Alzheimerȁ9;s disease pathogenesis. Multi-faceted effects of estrogens include improved cerebral metabolic profile and reduced oxidative stress through actions on mitochondria, suggesting that a womanȁ9;s endogenous and exogenous estrogen exposures during midlife and in the late post-menopause might favourably influence Alzheimer risk and symptoms. This prediction finds partial support in the clinical literature. As expected, early menopause induced by oophorectomy may increase cognitive vulnerability; however, there is no clear link between age at menopause and Alzheimer risk in other settings, or between natural menopause and memory loss. Further, among older post-menopausal women, initiating estrogen-containing hormone therapy increases dementia risk and probably does not improve Alzheimerȁ9;s disease symptoms. As suggested by the ȁ8;critical windowȁ9; or ȁ8;healthy cellȁ9; hypothesis, better outcomes might be expected from earlier estrogen exposures. Some observational results imply that effects of hormone therapy on Alzheimer risk are indeed modified by age at initiation, temporal proximity to menopause, or a womanȁ9;s health. However, potential methodological biases warrant caution in interpreting observational findings. Anticipated results from large, ongoing clinical trials [Early Versus Late Intervention Trial with Estradiol (ELITE), Kronos Early Estrogen Prevention Study (KEEPS)] will help settle whether midlife estrogen therapy improves midlife cognitive skills but not whether midlife estrogen exposures modify late-life Alzheimer risk. Estrogen effects on mitochondria adumbrate the potential relevance of estrogens to Alzheimerȁ9;s disease. However, laboratory models are inexact embodiments of Alzheimer pathogenesis and progression, making it difficult to surmise net effects of estrogen exposures. Research needs include better predictors of adverse cognitive outcomes, biomarkers for risks associated with hormone therapy, and tools for monitoring brain function and disease progression.
• Bandelow, S., Espeland, M. A., Henderson, V. W., Resnick, S. M., Wallace, R. B., Coker, L. H., Hogervorst, E., Gibbs, R. B., & Brinton, R. D. (2009). Identifying risk factors for cognitive change in the Women's Health Initiative: a neural networks approach. In Hormone, Cognition and Dementia: State of the Art and Emergent Therapeutic Strategies. Cambridge University Press. doi:10.1017/CBO9780511635700.003
• Brinton, R. (2009). The healthy cell bias of estrogen action through regulating glucose metabolism and mitochondrial function: Implications for prevention of Alzheimer's disease. In Hormones, Cognition and Dementia. doi:10.1017/CBO9780511635700.007
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  Editors' introduction Brinton provides a comprehensive review of the effects of estradiol on glycolytic enzymes and glucose metabolism in the brain and in neurons. Her analysis reveals a large body of corroborating evidence converging on the conclusion that estradiol promotes enhanced utilization of glucose in the brain, thereby helping neurons to meet the energy demands of neuronal activation. Seeing as how dysfunction of glucose metabolism and neuronal biogenetics are antecedents to Alzheimer's disease (AD), it is reasonable to speculate how the effects of estrogens on glucose metabolism might help stave off the disease. Her studies show, however, that as neurons become compromised such as in the context of aging and/or disease, the effects of estrogens can become deleterious and ultimately lead to the activation of apoptotic pathways and neuronal death. Hence the hypothesis that as neurons age and become increasingly stressed or compromised, the net effect of estrogens on oxidative metabolism and neuronal survival shifts from positive to negative. This healthy cell bias may explain some of the recent negative clinical results, and in particular how estrogenic therapy administered around the time of the perimenopause can be beneficial whereas the same therapy administered late in life and in the context of a developing pathology could be detrimental and result in significant cognitive decline.
• Hogervorst, E., Henderson, V. W., Gibbs, R. B., & Brinton, R. D. (2009). Chapter 12 -Clinical data of estrogen's effects in the central nervous system: estrogen and mood. In Hormones, Cognition and Dementia: State of the Art and Emergent Therapeutic Strategies(pp Chapter 12). doi:10.1017/CBO9780511635700.013
• Hogervorst, E., Henderson, V. W., Gibbs, R. B., & Brinton, R. D. (2009). Hormones, Cognition and Dementia: State of the Art and Emergent Therapeutic Strategies. In Preface. doi:10.1017/CBO9780511635700.001
• Hogervorst, E., Henderson, V. W., Gibbs, R. B., & Brinton, R. D. (2009). Progesterone regulation of neuroprotective estrogen actions. In Hormones, Cognition and Dementia: State of the Art and Emergent Therapeutic Strategies(pp Chapter 11). doi:10.1017/CBO9780511635700.012
• Hogervorst, E., Henderson, V. W., Gibbs, R. B., Brinton, R. D., & Brinton, R. D. (2009). Hormones, Cognition and Dementia: State pf tje Art and Emergent Therapeutic Strategies. In Hormones, Cognition and Dementia(pp Chapter 11). Cambridge University Press. doi:10.1017/CBO9780511635700.012
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  Hormones, cognition, and dementia : , Hormones, cognition, and dementia : , کتابخانه دیجیتال جندی شاپور اهواز
• Kawas, C. H., Corrada, M. M., Paganini-hill, A., Hogervorst, E., Henderson, V. W., Gibbs, R. B., & Brinton, R. D. (2009). Estrogen therapy – relationship to longevity and prevalent dementia in the oldest-old: the Leisure World Cohort Study and the 90+ Study. In Hormones, Cognition and Dementia State of the Art and Emergent Therapeutic Strategies. Cambridge University Press. doi:10.1017/CBO9780511635700.004
• Zhao, L., & Brinton, R. (2009). In search of estrogen alternatives for the brain. In Hormones, Cognition and Dementia: State of the Art and Emergent Therapeutic Strategies(pp 93-100). Cambridge University Press. doi:10.1017/CBO9780511635700.011
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  Editors' introduction This chapter briefly reviews recent advancements in the search for a non-feminizing estrogen alternative that can mimic estrogen's positive effects on cognitive health without eliciting an undesirable impact on reproductive and cardiovascular systems. The discussion focuses on two avenues of translational development, tissue-selective and subtype-selective estrogen receptor (ER) modulators (SERMs), in particular ERβ-selective phytoSERMs as a natural approach for potentially promoting neurological health and preventing age-associated cognitive impairment and risk of Alzheimer's disease in both genders. Estrogen for the female brain Postmenopausal women are prone to cognitive changes as a result of diminished serum levels of female sex hormones following menopause, which increase the risks for cognitive impairment and dementia such as Alzheimer's disease (AD). A large body of evidence suggests that estrogen therapy (ET) can potentially counteract these changes by sustaining the brain in a proactively defensive status against neurodegeneration (reviewed in Chapter 6). Until recently, this well documented concept has been complicated by the findings of the largest randomized and controlled clinical study, the Women's Health Initiative Memory Study (WHIMS), which was designed to evaluate the relationship between estrogen and cognition. It was found that ET was either to be of no benefit (estrogen-alone) or to afford a negative impact (estrogen plus progestin) on global cognition in postmenopausal women aged 65 years or older [1-4] (see also Chapters 1-5).
• Brinton, R. D., & Nilsen, J. (2001). Sex Hormones and their Brain Receptors. In International Encyclopedia of the Social & Behavioral Sciences. doi:10.1016/B0-08-043076-7/03453-7
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  Gonadal hormones exert a profound influence on brain development and function throughout the life span. Discoveries of estrogen and progesterone action on brain functions beyond reproduction has led to a resurgence of interest in these steroids and in their receptors. Recent advances in molecular genetics have led to the discovery of novel estrogen receptors and novel isoforms of both the estrogen and progesterone receptors. The emergence of compelling biochemical and electrophysiological data coupled with protein labeling have led to the identification of membrane receptors for sex steroids. These discoveries have greatly expanded our understanding of gonadal steroid hormone action in brain while also opening new avenues of exploration into the function of the novel genomic and membrane receptors for sex hormones in the nervous system. The understanding of gonadal steroid receptors will have direct impact on the development of therapeutics that will capitalize on the benefits of estrogens and progestins in sustaining cognitive function and preventing neuronal dysfunction.
• Mcewen, B. S., Brinton, R. E., Chao, H. M., Coirini, H., Gannon, M. N., Gould, E., O'callaghan, J. P., Spencer, R. L., Sakai, R. R., & Woolley, C. S. (1990). The Hippocampus: A Site for Modulatory Interactions Between Steroid Hormones, Neurotransmitters and Neuropeptides. In Neuroendocrine Perspectives(pp 93-131). Volume V111: Springer-Venjay, New York, NY. doi:10.1007/978-1-4612-3446-3_4
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  The brain is a dynamic and changing organ in which synapses, dendrites and the neurochemicals of synaptic neurotransmission are continually being renewed and remodeled during the entire lifespan of an individual. Gene activity, controlled by environmental signals and mediated by circulating hormones, is fundamental to this plasticity (1). Our understanding of these relationships has arisen in part from studies that have identified and characterized the receptor sites for adrenal, gonadal and thyroid hormones in the brain (2). Together with ongoing advances in many aspects of neuroscience, and in our understanding of how steroid and thyroid hormone receptors regulate gene expression (3,4), this information has stimulated a new field of investigation into how the brain changes in response to circulating hormones.

Journals/Publications

• Cortes-Flores, H., Torrandell-Haro, G., & Brinton, R. (2024). Association between CNS-active drugs and risk of Alzheimer’s and age-related neurodegenerative diseases. Frontiers in Psychiatry, 15. doi:10.3389/fpsyt.2024.1358568
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  Objective: As neuropsychiatric conditions can increase the risk of age-related neurodegenerative diseases (NDDs), the impact of CNS-active drugs on the risk of developing Alzheimer’s Disease (AD), non-AD dementia, Multiple Sclerosis (MS), Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) was investigated. Research design and methods: A retrospective cohort analysis of a medical claims dataset over a 10 year span was conducted in patients aged 60 years or older. Participants were propensity score matched for comorbidity severity and demographic parameters. Relative risk (RR) ratios and 95% confidence intervals (CI) were determined for age-related NDDs. Cumulative hazard ratios and treatment duration were determined to assess the association between CNS-active drugs and NDDs at different ages and treatment duration intervals. Results: In 309,128 patients who met inclusion criteria, exposure to CNS-active drugs was associated with a decreased risk of AD (0.86% vs 1.73%, RR: 0.50; 95% CI: 0.47-0.53; p
• Karp, J., Brinton, R., Fournier, J., Harding, L., Jha, M., Lenze, E., Mathew, S., Meltzer-Brody, S., Mohr, D., Riva-Posse, P., Wiechers, I., & Williams, N. (2024). Difficult to Treat Depression: Focus on Approach, Algorithms, and Access. The Journal of clinical psychiatry, 85(4). doi:10.4088/JCP.psprmdd2408ah
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  The pandemic refocused interest on the burden of depression across the lifespan; the increased efforts to prevent and treat depression are now a priority of health care systems, insurers, patient advocates, digital therapeutic engineers, telemedicine platforms, and community health agencies. However, the challenges of treating depression to remission in adult patients who do not respond to first, second, or third levels of oral pharmacotherapy remain. The increased prevalence of these conditions is at odds with the shrinking psychiatric workforce. Since addressing difficult to treat depression is situated in a rapidly evolving treatment landscape, The University of Arizona College of Medicine-Tucson Department of Psychiatry organized and hosted the Southwest Forum on Difficult to Treat Depression: Focus on Approach, Algorithms, and Access in July 2024. The Forum convened 11 internationally renowned experts in the science and treatment of depression, in particular difficult to treat depression, for a day of teaching and discussion. Based on their expertise, participants were asked to address one of the following three themes: (1) Novel Mechanism Approaches for Difficult to Treat Depression, (2) What Do I Do Next? Evidence-Informed Algorithms to Get Patients Better Faster, and (3) Access: Providing Comprehensive Depression Care Across the Spectrum of Clinical Severity.
• Mosconi, L., Nerattini, M., Matthews, D., Jett, S., Andy, C., Williams, S., Yepez, C., Zarate, C., Carlton, C., Fauci, F., Ajila, T., Pahlajani, S., Andrews, R., Pupi, A., Ballon, D., Kelly, J., Osborne, J., Nehmeh, S., Fink, M., , Berti, V., et al. (2024). In vivo brain estrogen receptor density by neuroendocrine aging and relationships with cognition and symptomatology. Scientific Reports, 14(1). doi:10.1038/s41598-024-62820-7
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  17β-estradiol, the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo brain 18F-fluoroestradiol (18F-FES) Positron Emission Tomography (PET) study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age, plasma estradiol and sex hormone binding globulin, and were highly consistent, correctly classifying all women as being postmenopausal or premenopausal. Higher ER density in target regions was associated with poorer memory performance for both postmenopausal and perimenopausal groups, and predicted presence of self-reported mood and cognitive symptoms after menopause. These findings provide novel insights on brain ER density modulation by female neuroendocrine aging, with clinical implications for women’s health.
• Mosconi, L., Williams, S., Carlton, C., Zarate, C., Boneu, C., Fauci, F., Ajila, T., Nerattini, M., Jett, S., Andy, C., Battista, M., Pahlajani, S., Osborne, J., Brinton, R., & Dyke, J. (2024). Sex-specific associations of serum cortisol with brain biomarkers of Alzheimer’s risk. Scientific Reports, 14(1). doi:10.1038/s41598-024-56071-9
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  Emerging evidence implicates chronic psychological stress as a risk factor for Alzheimer’s disease (AD). Herein, we examined the relationships between serum cortisol and multimodality brain AD biomarkers in 277 cognitively normal midlife individuals at risk for AD. Overall, higher cortisol was associated with lower total brain volume, lower glucose metabolism (CMRglc) in frontal cortex, and higher β-amyloid (Aβ) load in AD-vulnerable regions; and marginally associated with phosphocreatine to ATP ratios (PCr/ATP) in precuneus and parietal regions. Sex-specific modification effects were noted: in women, cortisol exhibited stronger associations with Aβ load and frontal CMRglc, the latter being more pronounced postmenopause. In men, cortisol exhibited stronger associations with gray matter volume and PCr/ATP measures. Higher cortisol was associated with poorer delayed memory in men but not in women. Results were adjusted for age, Apolipoprotein E (APOE) epsilon 4 status, midlife health factors, and hormone therapy use. These results suggest sex-specific neurophysiological responses to stress, and support a role for stress reduction in AD prevention.
• Mullins, A., Snider, J., Michael, B., Porter, L., Brinton, R., & Chilton, F. (2024). Impact of fish oil supplementation on plasma levels of highly unsaturated fatty acid-containing lipid classes and molecular species in American football athletes. Nutrition and Metabolism, 21(1). doi:10.1186/s12986-024-00815-x
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  Background: Previous studies have linked sports-related concussions and repeated subconcussive head impacts in contact sport athletes to elevated brain injury biomarkers. Docosahexaenoic acid (DHA), the primary omega-3 (n-3) highly unsaturated fatty acid (HUFA) in the brain, has shown neuroprotective effects in animal models after brain injury, but clinical research has shown mixed results. Methods: We conducted a randomized, double-blind, placebo-controlled study on 29 Division 1 collegiate American football players, exploring the impact of DHA (2.5 g) and eicosapentaenoic acid (EPA) (1.0 g) supplied as ethyl esters, on levels of plasma lipids shown to cross the blood-brain barrier. Dietary intake data was collected using food frequency questionnaires (FFQ). Complex lipids and unesterified fatty acids were isolated from plasma, separated via reversed-phase liquid chromatography and analyzed by targeted lipidomics analysis. Results: FFQ results indicated that participants had low dietary n-3 HUFA intake and high omega-6 (n-6):n-3 polyunsaturated fatty acids (PUFA) and HUFA ratios at baseline. After DHA + EPA supplementation, plasma lysophosphatidylcholine (LPC) containing DHA and EPA significantly increased at all timepoints (weeks 17, 21, and 26; p < 0.0001), surpassing placebo at Weeks 17 (p < 0.05) and 21 (p < 0.05). Phosphatidylcholine (PC) molecular species containing DHA or EPA, PC38:6 PC36:6, PC38:7, PC40:6, and PC40:8, increased significantly in the DHA + EPA treatment group at Weeks 17 (and 21. Plasma concentrations of non-esterified DHA and EPA rose post-supplementation in Weeks 17 and 21. Conclusions: This study demonstrates that n-3 HUFA supplementation, in the form of ethyl esters, increased the DHA and EPA containing plasma lipid pools the have the capacity to enrich brain lipids and the potential to mitigate the effects of sports-related concussions and repeated subconcussive head impacts. Trial Registration: All deidentified data are available at ClinicalTrials.gov #NCT0479207.
• Reyes-Reyes, E., Brown, J., Trial, M., Chinnasamy, D., Wiegand, J., Bradford, D., Brinton, R., & Rodgers, K. (2024). Vivaria housing conditions expose sex differences in brain oxidation, microglial activation, and immune system states in aged hAPOE4 mice. Experimental Brain Research, 242(3), 543-557. doi:10.1007/s00221-023-06763-x
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  Apolipoprotein E ε4 allele (APOE4) is the predominant genetic risk factor for late-onset Alzheimer’s disease (AD). APOE4 mouse models have provided advances in the understanding of disease pathogenesis, but unaccounted variables like rodent housing status may hinder translational outcomes. Non-sterile aspects like food and bedding can be major sources of changes in rodent microflora. Alterations in intestinal microbial ecology can cause mucosal barrier impairment and increase pro-inflammatory signals. The present study examined the role of sterile and non-sterile food and housing on redox indicators and the immune status of humanized-APOE4 knock-in mice (hAPOe4). hAPOE4 mice were housed under sterile conditions until 22 months of age, followed by the transfer of a cohort of mice to non-sterile housing for 2 months. At 24 months of age, the redox/immunologic status was evaluated by flow cytometry/ELISA. hAPOE4 females housed under non-sterile conditions exhibited: (1) higher neuronal and microglial oxygen radical production and (2) lower CD68+ microglia (brain) and CD8+ T cells (periphery) compared to sterile-housed mice. In contrast, hAPOE4 males in non-sterile housing exhibited: (1) higher MHCII+ microglia and CD11b+CD4+ T cells (brain) and (2) higher CD11b+CD4+ T cells and levels of lipopolysaccharide-binding protein and inflammatory cytokines in the periphery relative to sterile-housed mice. This study demonstrated that sterile vs. non-sterile housing conditions are associated with the activation of redox and immune responses in the brain and periphery in a sex-dependent manner. Therefore, housing status may contribute to variable outcomes in both the brain and periphery.
• Vitali, F., Torrandell-Haro, G., Branigan, G., Aristizabal, J., Reiman, E., Bedrick, E., Brinton, R., & Weinkauf, C. (2024). Asymptomatic carotid artery stenosis is associated with increased Alzheimer’s disease and non-Alzheimer’s disease dementia risk. Stroke and Vascular Neurology. doi:10.1136/svn-2024-003164
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  Background In the absence of a cerebrovascular accident, whether asymptomatic extracranial carotid atherosclerotic disease (aECAD) affects Alzheimer’s disease (AD) and non-AD dementia risk is not clear. Understanding whether aECAD is associated with an increased risk for AD is important as it is present in roughly 10% of the population over 60 and could represent a modifiable risk factor for AD and non-AD dementia. Methods This retrospective cohort study analysed Mariner insurance claims. Enrolment criteria included patients aged 55 years or older with at least 5 years of data and no initial dementia diagnosis. Subjects with and without aECAD were evaluated for subsequent AD and non-AD dementia diagnoses. Propensity score matching was performed using confounding factors identified by logistic regression. χ2 tests and Kaplan-Meier survival curves were used to evaluate the impact of aECAD diagnosis on AD and non-AD dementia risk over time. Results 767 354 patients met enrolment criteria. After propensity score matching, 62 963 subjects with aECAD and 62 963 subjects without ECAD were followed through data records. The aECAD cohort exhibited an increased relative risk of 1.22 (95% CI 1.15 to 1.29, p
• Andrews, R., Andy, C., Ballon, D., Berti, V., Brinton, R. D., Carlton, C., Dyke, J., Fink, M., Havryliuk, Y., Jett, S., Kelly, J., Kodancha, V., Loeb-Zeitlin, S., Matthews, D., Mosconi, L., Nehmeh, S., Nerattini, M., Osborne, J., Pahlajani, S., , Pupi, A., et al. (2023).

  In vivo Brain Estrogen Receptor Expression By Neuroendocrine Aging And Relationships With Gray Matter Volume, Bio-Energetics, and Clinical Symptomatology

  . Research Square. doi:10.21203/rs.3.rs-2573335/v1
• Branigan, G., Haro, G. T., Vitali, F., Brinton, R., & Rodgers, K. (2023). Implications for Age and Sex Differences on Anti-Hyperglycemic Therapy Exposure and Incidence of Newly Diagnosed Multiple Sclerosis in Propensity Score Matched Type 2 Diabetics (P9-3.007). Neurology, 100(17_supplement_2). doi:10.1212/wnl.0000000000202117
• Branigan, G., Torrandell-Haro, G., Chen, S., Shang, Y., Perez-Miller, S., Mao, Z., Padilla-Rodriguez, M., Cortes-Flores, H., Vitali, F., & Brinton, R. (2023). Breast cancer therapies reduce risk of Alzheimer's disease and promote estrogenic pathways and action in brain. iScience, 26(11). doi:10.1016/j.isci.2023.108316
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  Worldwide, an ever-increasing number of women are prescribed estrogen-modulating therapies (EMTs) for the treatment of breast cancer. In parallel, aging of the global population of women will contribute to risk of both breast cancer and Alzheimer's disease. To address the impact of anti-estrogen therapies on risk of Alzheimer's and neural function, we conducted medical informatic and molecular pharmacology analyses to determine the impact of EMTs on risk of Alzheimer's followed by determination of EMT estrogenic mechanisms of action in neurons. Collectively, these data provide both clinical and mechanistic data indicating that select EMTs exert estrogenic agonist action in neural tissue that are associated with reduced risk of Alzheimer's disease while simultaneously acting as effective estrogen receptor antagonists in breast.
• Chang, R., Trushina, E., Zhu, K., Zaidi, S., Lau, B., Kueider-Paisley, A., Moein, S., He, Q., Alamprese, M., Vagnerova, B., Tang, A., Vijayan, R., Liu, Y., Saykin, A., Brinton, R., & Kaddurah-Daouk, R. (2023). Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease. Alzheimer's and Dementia, 19(2), 518-531. doi:10.1002/alz.12675
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  Introduction: Late-onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease characterized by multiple progressive stages, glucose metabolic dysregulation, Alzheimer's disease (AD) pathology, and inexorable cognitive decline. Discovery of metabolic profiles unique to sex, apolipoprotein E (APOE) genotype, and stage of disease progression could provide critical insights for personalized LOAD medicine. Methods: Sex- and APOE-specific metabolic networks were constructed based on changes in 127 metabolites of 656 serum samples from the Alzheimer's Disease Neuroimaging Initiative cohort. Results: Application of an advanced analytical platform identified metabolic drivers and signatures clustered with sex and/or APOE ɛ4, establishing patient-specific biomarkers predictive of disease state that significantly associated with cognitive function. Presence of the APOE ɛ4 shifts metabolic signatures to a phosphatidylcholine-focused profile overriding sex-specific differences in serum metabolites of AD patients. Discussion: These findings provide an initial but critical step in developing a diagnostic platform for personalized medicine by integrating metabolomic profiling and cognitive assessments to identify targeted precision therapeutics for AD patient subgroups through computational network modeling.
• Jett, S., Dyke, J., Yepez, C., Zarate, C., Carlton, C., Schelbaum, E., Jang, G., Pahlajani, S., Williams, S., Brinton, R., & Mosconi, L. (2023). Effects of sex and APOE ε4 genotype on brain mitochondrial high-energy phosphates in midlife individuals at risk for Alzheimer’s disease: A 31Phosphorus MR spectroscopy study. PLoS ONE, 18(2). doi:10.1371/journal.pone.0281302
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  Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer’s disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40–65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4 + men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men’s brains to a similar metabolic range as women’s brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.
• Merlini, S., Vitali, F., & Brinton, R. D. (2023). Sex and APOE differences in Alzheimer’s Disease‐On‐Ramp risk factor profiles: Are all risk factors for Alzheimer’s Disease created equal?. Alzheimer's & Dementia, 19(S24). doi:10.1002/alz.082316
• Mi, Y., Qi, G., Vitali, F., Shang, Y., Raikes, A., Wang, T., Jin, Y., Brinton, R., Gu, H., & Yin, F. (2023). Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration. Nature Metabolism, 5(3), 445-465. doi:10.1038/s42255-023-00756-4
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  Astrocytes provide key neuronal support, and their phenotypic transformation is implicated in neurodegenerative diseases. Metabolically, astrocytes possess low mitochondrial oxidative phosphorylation (OxPhos) activity, but its pathophysiological role in neurodegeneration remains unclear. Here, we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of Alzheimer’s disease (AD), including synaptic loss, neuroinflammation, demyelination and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl-CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid-laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia through IL-3 signalling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Along with LD accumulation and impaired FA degradation manifested in an AD mouse model, we reveal a lipid-centric, AD-resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.
• Wang, T., Chen, S., Mao, Z., Shang, Y., & Brinton, R. (2023). Allopregnanolone pleiotropic action in neurons and astrocytes: calcium signaling as a unifying mechanism. Frontiers in Endocrinology, 14. doi:10.3389/fendo.2023.1286931
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  Objective: Allopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration, increased glucose metabolism, mitochondrial respiration and biogenesis, improved cognitive function, and reduction of both inflammation and Alzheimer’s disease (AD) pathology. Because the breadth of Allo-induced responses requires activation of multiple systems of biology in the absence of an Allo-specific nuclear receptor, analyses were conducted in both neurons and astrocytes to identify unifying systems and signaling pathways. Methods: Mechanisms of Allo action were investigated in embryonic hippocampal neurons and astrocytes cultured in an Aging Model (AM) media. Cellular morphology, mitochondrial function, and transcriptomics were investigated followed by mechanistic pathway analyses. Results: In hippocampal neurons, Allo significantly increased neurite outgrowth and synaptic protein expression, which were paralleled by upregulated synaptogenesis and long-term potentiation gene expression profiles. Mechanistically, Allo induced Ca2+/CREB signaling cascades. In parallel, Allo significantly increased maximal mitochondrial respiration, mitochondrial membrane potential, and Complex IV activity while reducing oxidative stress, which required both the GABAA and L-type Ca2+ channels. In astrocytes, Allo increased ATP generation, mitochondrial function and dynamics while reducing oxidative stress, inflammasome indicators, and apoptotic signaling. Mechanistically, Allo regulation of astrocytic mitochondrial function required both the GABAA and L-type Ca2+ channels. Furthermore, Allo activated NRF1-TFAM signaling and increased the DRP1/OPA1 protein ratio, which led to increased mitochondrial biogenesis and dynamics. Conclusion: Collectively, the cellular, mitochondrial, transcriptional, and pharmacological profiles provide evidence in support of calcium signaling as a unifying mechanism for Allo pleiotropic actions in the brain.
• Branigan, G. L., Gelmann, E. P., Vitali, F., Torrandell-haro, G., Soto, M., Rodgers, K. E., & Brinton, R. D. (2022). Androgen-targeting therapeutics mitigate the adverse effect of GnRH agonist on the risk of neurodegenerative disease in men treated for prostate cancer.. Cancer medicine, 11(13), 2687-2698. doi:10.1002/cam4.4650
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  Prostate cancer and multiple neurodegenerative diseases (NDD) share an age-associated pattern of onset. Therapy of prostate cancer is known to impact cognitive function. The objective of this study was to determine the impact of multiple classes of androgen-targeting therapeutics (ATT) on the risk of NDD..A retrospective cohort study of men aged 45 and older with prostate within the US-based Mariner claims data set between January 1 and 27, 2021. A propensity score approach was used to minimize measured and unmeasured selection bias. Disease risk was determined using Kaplan-Meier survival analyses..Of the 1,798,648 men with prostate cancer, 209,722 met inclusion criteria. Mean (SD) follow-up was 6.4 (1.8) years. In the propensity score-matched population, exposure to ATT was associated with a minimal increase in NDD incidence (relative risk [RR], 1.07; 95% CI, 1.05-1.10; p 
• Branigan, G., Haro, G. T., Rodgers, K., & Brinton, R. (2022). A Retrospective Study of Androgen Targeting Therapies and Incidence of Neurodegenerative Outcomes in Male Prostate Cancer Patients: Implications for Clinic to Bench Translation (S15.009). Neurology, 98(18_supplement). doi:10.1212/wnl.98.18_supplement.1274
• Branigan, G., Torrandell-Haro, G., Vitali, F., Brinton, R., & Rodgers, K. (2022). Age and sex differences on anti-hyperglycemic medication exposure and risk of newly diagnosed multiple sclerosis in propensity score matched type 2 diabetics. Heliyon, 8(10). doi:10.1016/j.heliyon.2022.e11196
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  Background: The association between exposure to anti-hyperglycemic medications (A-HgM) for Type 2 Diabetes Mellitus (T2D) treatment and Multiple Sclerosis (MS) in T2D patients is unclear. Methods: This retrospective cohort analysis used the Mariner claims database. Patient records were surveyed for a diagnosis of MS starting 12 months after diagnosis of T2D. Patients were required to be actively enrolled in the Mariner claims records for six months prior and at least three years after the diagnosis of T2D without a history of previous neurodegenerative disease. Survival analysis was used to determine the association between A-HgM exposure and diagnosis of MS. A propensity score approach was used to minimize measured and unmeasured selection bias. The analyses were conducted between January 1st and April 28th, 2021. Findings: In T2D patients younger than 45, A-HgM exposure was associated with a reduced risk of developing MS (RR: 0.22, 95%CI: 0.17–0.29, p-value
• Brinton, R. D., Branigan, G. L., Torrandell‐Haro, G., & Rodgers, K. E. (2022). Statin responder analysis for precision prevention of Alzheimer’s Disease. Alzheimer's & Dementia, 18(S11). doi:10.1002/alz.068305
• Brinton, R. D., Nerattini, M., Rubino, F., Jett, S., Andy, C., Yepez, C. B., Zarate, C., Carlton, C., Kodancha, V., Loeb-Zeitlin, S., Havryliuk, Y., Pahlajani, S., Williams, S., Berti, V., Dyke, J., & Mosconi, L. (2022). Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer’s disease in midlife women. Research Square. doi:10.21203/rs.3.rs-2351642/v1
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  Menopause has been implicated in women’s greater life-time risk for Alzheimer’s disease (AD) due to its disruptive action on multiple neurobiological mechanisms resulting in amyloid-β deposition and synaptic dysfunction.While these effects are typically attributed to declines in estradiol, mechanistic analyses implicate pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), in AD pathology. In transgenic mouse models of AD, increasing FSH and LH accelerate amyloid-β deposition, while inhibiting these hormones prevents emergence of AD lesions and neurodegeneration. Herein, we take a translational approach to show that, among midlife women at risk for AD, FSH elevations over the menopause transition are associated with higher amyloid-β burden, and both FSH and LH increases are associated with lower gray matter volume in AD-vulnerable brain regions. Results were independent of age, hormone therapy usage, and plasma estradiol levels. These findings provide novel therapeutic targets for sex-based precision medicine strategies for AD prevention.
• Brinton, R. D., Wang, T., Mao, Z., Delatorre, N., & Wiegand, J. L. (2022). Translational potential of JAX humanized‐APOE mice model: Accelerated midlife endocrine aging in hAPOEε4/4 females. Alzheimer's & Dementia, 18(S4). doi:10.1002/alz.067969
• Chilton, F., Brinton, R., Raikes, A., Lopez, C., Hernadez, G., Wang, Y., Polian, D., Skulas-Ray, A. C., Ovando, V., Wood, A., Cummings, D., & Graham, S. (2021). Effect of fish oil supplementation on biomarkers of axonal injury and acute inflammation in American football players. Journal of Applied Physiology, Nutrition, and Metabolism.
• Hernandez, G., & Brinton, R. (2022). Allopregnanolone: Regenerative therapeutic to restore neurological health. Neurobiology of Stress, 21. doi:10.1016/j.ynstr.2022.100502
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  Chronic stress has been proposed as a driver of altered brain structure and function, including the pathogenesis of neurodegenerative diseases and a driver of disease progression. A key outcome of stress in the brain is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicate failed resilience. Neuroendocrine homeostasis and stress response are mainly dependent upon the functioning of the hypothalamic–pituitary–adrenal axis. Neurosteroids will fluctuate depending on whether the stress is acute or chronic. Advancements in neurosteroid research have led to the identification of multiple targets for drug development, but the most promising innovative target may be neurogenesis, given its potential impact in neurodegenerative disorders like Alzheimer's disease. Allopregnanolone is an endogenous pregnane neurosteroid and a reduced metabolite of progesterone, which acts as a potent allosteric modulator and direct activator of the GABA-chloride channel complex. Perhaps the most intriguing finding related to the potential therapeutic effects of allopregnanolone is its potential to promote neuroregeneration.
• Jett, S., Dyke, J., Andy, C., Schelbaum, E., Jang, G., Boneu Yepez, C., Pahlajani, S., Diaz, I., Diaz Brinton, R., & Mosconi, L. (2022). Sex and menopause impact 31P-Magnetic Resonance Spectroscopy brain mitochondrial function in association with 11C-PiB PET amyloid-beta load. Scientific Reports, 12(1). doi:10.1038/s41598-022-26573-5
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  Increasing evidence implicates sex and endocrine aging effects on brain bioenergetic aging in the greater lifetime risk of Alzheimer’s disease (AD) in women. We conducted 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to assess the impact of sex and menopause on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters/phosphodiesters (PME/PDE)] in 216 midlife cognitively normal individuals at risk for AD, 80% female. Ninety-seven participants completed amyloid-beta (Aβ) 11C-PiB PET. Women exhibited higher ATP utilization than men in AD-vulnerable frontal, posterior cingulate, fusiform, medial and lateral temporal regions (p < 0.001). This profile was evident in frontal cortex at the pre-menopausal and peri-menopausal stage and extended to the other regions at the post-menopausal stage (p = 0.001). Results were significant after multi-variable adjustment for age, APOE-4 status, midlife health indicators, history of hysterectomy/oophorectomy, use of menopause hormonal therapy, and total intracranial volume. While associations between ATP/PCr and Aβ load were not significant, individuals with the highest Aβ load were post-menopausal and peri-menopausal women with ATP/PCr ratios in the higher end of the distribution. No differences in Pi/PCr, Pi/ATP or PME/PDE were detected. Outcomes are consistent with dynamic bioenergetic brain adaptations that are associated with female sex and endocrine aging.
• McLean, J., Bhattrai, A., Vitali, F., Raikes, A., Wiegand, J., & Brinton, R. (2022). Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease. Learning and Memory, 29(9), 321-331. doi:10.1101/lm.053588.122
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  Age, genetics, and chromosomal sex have been identified as critical risk factors for late-onset Alzheimer's disease (LOAD). The predominant genetic risk factor for LOAD is the apolipoprotein E ε4 allele (APOE4), and the prevalence of LOAD is higher in females. However, the translational validity of APOE4 mouse models for AD-related cognitive impairment remains to be fully determined. The present study investigated the role of both sex and genotype on learning and memory in aged, humanized APOE knock-in mice. Aged (23.27 mo ± 1.21 mo; 39 male/37 female) APOE3/3, APOE3/4, and APOE4/4 mice performed a novel object recognition (NOR) assay. Task-related metrics were analyzed using two-way sex by genotype ANOVAs. Sex differences were more prominent relative to APOE genotype. Prior to NOR, female mice exhibited thigmotaxic center zone avoidance during the open field task relative to males, regardless of genotype. Within object familiarization and NOR tasks, females had greater object interaction and locomotion. Interestingly, only APOE4/4 females on average recognized the novel object. These results suggest that APOE4, although strongly related to LOAD pathogenesis, does not drive cognitive decline in the absence of other risk factors even in very aged mice. Chromosomal sex is a key driver of behavioral phenotypes and thus is a critical variable for translatability of interventions designed to preserve learning and memory in animal models of LOAD. Last, there was a very high degree of variability in behavioral performance across APOE genotypes. A cluster analysis of the behavioral data revealed a low-activity and a high-activity cluster. APOE4 carriers were overrepresented in the low-activity cluster, while male:female distributions did not differ. Collectively, the behavioral data indicate that chromosomal sex has the greatest impact on behavioral phenotype, and APOE4 carrier status may confer greater risk for cognitive decline in some animals.
• Mullins, V., Graham, S., Cummings, D., Wood, A., Ovando, V., Skulas-Ray, A., Polian, D., Wang, Y., Hernandez, G., Lopez, C., Raikes, A., Brinton, R., & Chilton, F. (2022). Effects of Fish Oil on Biomarkers of Axonal Injury and Inflammation in American Football Players: A Placebo-Controlled Randomized Controlled Trial. Nutrients, 14(10). doi:10.3390/nu14102139
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  There are limited studies on neuroprotection from repeated subconcussive head impacts (RSHI) following docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) supplementation in contact sports athletes. We performed a randomized, placebo-controlled, double-blinded, parallel-group design trial to determine the impact of 26 weeks of DHA+EPA supplementation (n = 12) vs. placebo (high-oleic safflower oil) (n = 17) on serum concentrations of neurofilament light (NfL), a biomarker of axonal injury, and inflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a)) in National Collegiate Athletic Association Division I American football athletes. DHA+EPA supplementation increased (p < 0.01) plasma DHA and EPA concentrations throughout the treatment period. NfL concentrations increased from baseline to week 26 in both groups (treatment (
• Schelbaum, E., Pahlajani, S., Niotis, K., Mosconi, L., Malviya, N., Loeb-zeitlin, S., Jett, S., Jang, G., Jahan, E., Isaacson, R., Hristov, H., Havryliuk, Y., Clancy, K., & Brinton, R. D. (2022). Endogenous and Exogenous Estrogen Exposures: How Women's Reproductive Health Can Drive Brain Aging and Inform Alzheimer's Prevention.. Frontiers in aging neuroscience, 14, 831807. doi:10.3389/fnagi.2022.831807
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  After advanced age, female sex is the major risk factor for late-onset Alzheimer's disease (AD), the most common cause of dementia affecting over 24 million people worldwide. The prevalence of AD is higher in women than in men, with postmenopausal women accounting for over 60% of all those affected. While most research has focused on gender-combined risk, emerging data indicate sex and gender differences in AD pathophysiology, onset, and progression, which may help account for the higher prevalence in women. Notably, AD-related brain changes develop during a 10-20 year prodromal phase originating in midlife, thus proximate with the hormonal transitions of endocrine aging characteristic of the menopause transition in women. Preclinical evidence for neuroprotective effects of gonadal sex steroid hormones, especially 17β-estradiol, strongly argue for associations between female fertility, reproductive history, and AD risk. The level of gonadal hormones to which the female brain is exposed changes considerably across the lifespan, with relevance to AD risk. However, the neurobiological consequences of hormonal fluctuations, as well as that of hormone therapies, are yet to be fully understood. Epidemiological studies have yielded contrasting results of protective, deleterious and null effects of estrogen exposure on dementia risk. In contrast, brain imaging studies provide encouraging evidence for positive associations between greater cumulative lifetime estrogen exposure and lower AD risk in women, whereas estrogen deprivation is associated with negative consequences on brain structure, function, and biochemistry. Herein, we review the existing literature and evaluate the strength of observed associations between female-specific reproductive health factors and AD risk in women, with a focus on the role of endogenous and exogenous estrogen exposures as a key underlying mechanism. Chief among these variables are reproductive lifespan, menopause status, type of menopause (spontaneous vs. induced), number of pregnancies, and exposure to hormonal therapy, including hormonal contraceptives, hormonal therapy for menopause, and anti-estrogen treatment. As aging is the greatest risk factor for AD followed by female sex, understanding sex-specific biological pathways through which reproductive history modulates brain aging is crucial to inform preventative and therapeutic strategies for AD.
• Shi, Y., Schneider, L. S., Raikes, A. C., Matthews, D. C., Lukic, A. S., Law, M., Hernandez, G. D., & Brinton, R. D. (2022). Exploratory imaging outcomes of a phase 1b/2a clinical trial of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: Structural effects and functional connectivity outcomes.. Alzheimer's & dementia (New York, N. Y.), 8(1), e12258. doi:10.1002/trc2.12258
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  Allopregnanolone (ALLO), an endogenous neurosteroid, promoted neurogenesis and oligogenesis and restored cognitive function in animal models of Alzheimer's disease (AD). Based on these discovery research findings, we conducted a randomized-controlled phase 1b/2a multiple ascending dose trial of ALLO in persons with early AD (NCT02221622) to assess safety, tolerability, and pharmacokinetics. Exploratory imaging outcomes to determine whether ALLO impacted hippocampal structure, white matter integrity, and functional connectivity are reported..Twenty-four individuals participated in the trial (n = 6 placebo; n = 18 ALLO) and underwent brain magnetic resonance imaging (MRI) before and after 12 weeks of treatment. Hippocampal atrophy rate was determined from volumetric MRI, computed as rate of change, and qualitatively assessed between ALLO and placebo sex, apolipoprotein E (APOE) ε4 allele, and ALLO dose subgroups. White matter microstructural integrity was compared between placebo and ALLO using fractional and quantitative anisotropy (QA). Changes in local, inter-regional, and network-level functional connectivity were also compared between groups using resting-state functional MRI..Rate of decline in hippocampal volume was slowed, and in some cases reversed, in the ALLO group compared to placebo. Gain of hippocampal volume was evident in APOE ε4 carriers (range: 0.6% to 7.8% increased hippocampal volume). Multiple measures of white matter integrity indicated evidence of preserved or improved integrity. ALLO significantly increased fractional anisotropy (FA) in 690 of 690 and QA in 1416 of 1888 fiber tracts, located primarily in the corpus callosum, bilateral thalamic radiations, and bilateral corticospinal tracts. Consistent with structural changes, ALLO strengthened local, inter-regional, and network level functional connectivity in AD-vulnerable regions, including the precuneus and posterior cingulate, and network connections between the default mode network and limbic system..Indicators of regeneration from previous preclinical studies and these exploratory MRI-based outcomes from this phase 1b/2a clinical cohort support advancement to a phase 2 proof-of-concept efficacy clinical trial of ALLO as a regenerative therapeutic for mild AD (REGEN-BRAIN study; NCT04838301).
• Stephenson, D., Ollivier, C., Brinton, R., & Barrett, J. (2022). Can Innovative Trial Designs in Orphan Diseases Drive Advancement of Treatments for Common Neurological Diseases?. Clinical pharmacology and therapeutics, 111(4), 799-806. doi:10.1002/cpt.2528
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  Global regulatory agencies have transformed their approach to approvals in their processes for formal review of the safety and efficacy of new drugs. Opportunities for innovation have expanded because of the coronavirus disease 2019 (COVID-19) pandemic. Several regulatory-led initiatives have progressed rapidly during the past year, including patient-focused drug development, model-informed drug development, real-world evidence, and complex innovative trial designs. Collectively, these initiatives have accelerated the rate of approvals. Despite demands to focus on urgent needs imposed by the COVID-19 pandemic, the number of new drug approvals over the past year, particularly for rare diseases, has outpaced expectations. Advancing therapeutics for nervous system disorders requires adaptive strategies that align with rapid developments in the field. Three relentlessly progressive diseases, amyotrophic lateral sclerosis, Duchenne muscular dystrophy, and Parkinson's disease are in urgent need of new treatments. Herein, we propose new regulatory initiatives, including innovative trial designs and patient-focused drug development that accelerate clinical trial conduct while meeting critical regulatory requirements for therapeutic approval.
• Tang, X., Brinton, R., Chen, Z., Farland, L., Klimentidis, Y., Migrino, R., Reaven, P., Rodgers, K., & Zhou, J. (2022). Use of oral diabetes medications and the risk of incident dementia in US veterans aged ≥60 years with type 2 diabetes. BMJ Open Diabetes Research and Care, 10(5). doi:10.1136/bmjdrc-2022-002894
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  Introduction Studies have reported that antidiabetic medications (ADMs) were associated with lower risk of dementia, but current findings are inconsistent. This study compared the risk of dementia onset in patients with type 2 diabetes (T2D) treated with sulfonylurea (SU) or thiazolidinedione (TZD) to patients with T2D treated with metformin (MET). Research design and methods This is a prospective observational study within a T2D population using electronic medical records from all sites of the Veterans Affairs Healthcare System. Patients with T2D who initiated ADM from January 1, 2001, to December 31, 2017, were aged ≥60 years at the initiation, and were dementia-free were identified. A SU monotherapy group, a TZD monotherapy group, and a control group (MET monotherapy) were assembled based on prescription records. Participants were required to take the assigned treatment for at least 1 year. The primary outcome was all-cause dementia, and the two secondary outcomes were Alzheimer's disease and vascular dementia, defined by International Classification of Diseases (ICD), 9th Revision, or ICD, 10th Revision, codes. The risks of developing outcomes were compared using propensity score weighted Cox proportional hazard models. Results Among 559 106 eligible veterans (mean age 65.7 (SD 8.7) years), the all-cause dementia rate was 8.2 cases per 1000 person-years (95% CI 6.0 to 13.7). After at least 1 year of treatment, TZD monotherapy was associated with a 22% lower risk of all-cause dementia onset (HR 0.78, 95% CI 0.75 to 0.81), compared with MET monotherapy, and 11% lower for MET and TZD dual therapy (HR 0.89, 95% CI 0.86 to 0.93), whereas the risk was 12% higher for SU monotherapy (HR 1.12 95% CI 1.09 to 1.15). Conclusions Among patients with T2D, TZD use was associated with a lower risk of dementia, and SU use was associated with a higher risk compared with MET use. Supplementing SU with either MET or TZD may partially offset its prodementia effects. These findings may help inform medication selection for elderly patients with T2D at high risk of dementia.
• Torrandell-Haro, G., Branigan, G., Brinton, R., & Rodgers, K. (2022). Association Between Specific Type 2 Diabetes Therapies and Risk of Alzheimer’s Disease and Related Dementias in Propensity-Score Matched Type 2 Diabetic Patients. Frontiers in Aging Neuroscience, 14. doi:10.3389/fnagi.2022.878304
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  Objective: We sought to determine the impact of Type 2 Diabetes Mellitus (T2D) anti-hyperglycemic medications (A-HgM) on risk of Alzheimer’s disease (AD) and related dementias (ADRD) outcomes including vascular dementia, and non-AD dementia such as frontotemporal, Lewy body, and mixed etiology dementias. Research Design and Methods: This retrospective cohort study used the US-based Mariner claims dataset. 1,815,032 T2D participants 45 years and older with records 6 months prior and at least 3 years after the diagnosis of T2D were included. Claims were surveyed for a diagnosis of AD and ADRD 12 months post T2D diagnosis. A propensity score approach was used to minimize selection bias. Analyses were conducted between January 1st and February 28th, 2021. Results: In this cohort study A-HgM exposure was associated with decreased diagnosis of AD (RR, 0.61; 95% CI, 0.59–0.62; p < 0.001), vascular dementia (RR, 0.72; 95% CI, 0.69–0.74; p < 0.001) and non-AD dementia (RR, 0.67; 95% CI, 0.66–0.68; p < 0.001). Metformin was associated with the greatest risk reduction and insulin with the least reduction in risk compared to patients not receiving A-HgM for ADRD risk. Of interest, patients with a diagnosis of AD, while either on metformin or insulin, were older in age and predominately female, than individuals on these drugs that did not develop AD. Mean (SD) follow-up was 6.2 (1.8) years. Conclusion: After controlling for age, sex, and comorbidities, A-HgM in patients with T2D was associated with a reduced risk of AD and ADRD. These findings provide evidence in support of T2D as a risk factor for AD and ADRD and the beneficial impact of early and effective control of hyperglycemia to mitigate risk.
• Yin, F., Wang, Y., Wang, T., Vitali, F., Soto, M., Rodgers, K. E., Mosconi, L., Mishra, A., & Brinton, R. D. (2022). A tale of two systems: Lessons learned from female mid-life aging with implications for Alzheimer's prevention & treatment.. Ageing research reviews, 74, 101542. doi:10.1016/j.arr.2021.101542
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  Neurological aging is frequently viewed as a linear process of decline, whereas in reality, it is a dynamic non-linear process. The dynamic nature of neurological aging is exemplified during midlife in the female brain. To investigate fundamental mechanisms of midlife aging that underlie risk for development of Alzheimer's disease (AD) in late life, we investigated the brain at greatest risk for the disease, the aging female brain. Outcomes of our research indicate that mid-life aging in the female is characterized by the emergence of three phases: early chronological (pre-menopause), endocrinological (peri-menopause) and late chronological (post-menopause) aging. The endocrinological aging program is sandwiched between early and late chronological aging. Throughout the three stages of midlife aging, two systems of biology, metabolic and immune, are tightly integrated through a network of signaling cascades. The network of signaling between these two systems of biology underlie an orchestrated sequence of adaptative starvation responses that shift the brain from near exclusive dependence on a single fuel, glucose, to utilization of an auxiliary fuel derived from lipids, ketone bodies. The dismantling of the estrogen control of glucose metabolism during mid-life aging is a critical contributor to the shift in fuel systems and emergence of dynamic neuroimmune phenotype. The shift in fuel reliance, puts the largest reservoir of local fatty acids, white matter, at risk for catabolism as a source of lipids to generate ketone bodies through astrocytic beta oxidation. APOE4 genotype accelerates the tipping point for emergence of the bioenergetic crisis. While outcomes derived from research conducted in the female brain are not directly translatable to the male brain, the questions addressed in a female centric program of research are directly applicable to investigation of the male brain. Like females, males with AD exhibit deficits in the bioenergetic system of the brain, activation of the immune system and hallmark Alzheimer's pathologies. The drivers and trajectory of mechanisms underlying neurodegeneration in the male brain will undoubtedly share common aspects with the female in addition to factors unique to the male. Preclinical and clinical evidence indicate that midlife endocrine aging can also be a transitional bridge to autoimmune disorders. Collectively, the data indicate that endocrinological aging is a critical period "tipping point" in midlife which can initiate emergence of the prodromal stage of late-onset-Alzheimer's disease. Interventions that target both immune and metabolic shifts that occur during midlife aging have the potential to alter the trajectory of Alzheimer's risk in late life. Further, to achieve precision medicine for AD, chromosomal sex is a critical variable to consider along with APOE genotype, other genetic risk factors and stage of disease.
• Branigan, G. L., Torrandell-haro, G., Rodgers, K. E., & Brinton, R. D. (2021). Reduction of risk of development of Alzheimer’s disease and related dementias in patients with type 2 diabetes by drugs to treat hyperglycemia. Alzheimer's & Dementia, 17(S10). doi:10.1002/alz.055666
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  Alzheimer’s Disease and Related Dementias (ADRD) are progressive neurodegenerative disorders that manifest in reduced cognition, executive function and memory impairments. Type 2 Diabetes (T2D) is suggested to be a risk factor for the development of ADRD. In this study, we evaluated the effects of anti-hyperglycemic medications (HM) to treat hyperglycemia in T2D patients on the incidence of newly diagnosed ADRD.
• Brinton, R. D., & Bacon, E. R. (2021). Epigenetics of the developing and aging brain: Mechanisms that regulate onset and outcomes of brain reorganization.. Neuroscience and biobehavioral reviews, 125, 503-516. doi:10.1016/j.neubiorev.2021.02.040
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  Brain development is a life-long process that encompasses several critical periods of transition, during which significant cognitive changes occur. Embryonic development, puberty, and reproductive senescence are all periods of transition that are hypersensitive to environmental factors. Rather than isolated episodes, each transition builds upon the last and is influenced by consequential changes that occur in the transition before it. Epigenetic marks, such as DNA methylation and histone modifications, provide mechanisms by which early events can influence development, cognition, and health outcomes. For example, parental environment influences imprinting patterns in gamete cells, which ultimately impacts gene expression in the embryo which may result in hypersensitivity to poor maternal nutrition during pregnancy, raising the risks for cognitive impairment later in life. This review explores how epigenetics induce and regulate critical periods, and also discusses how early environmental interactions prime a system towards a particular health outcome and influence susceptibility to disease or cognitive impairment throughout life.
• Brinton, R. D., Dagliati, A., Peek, N., & Geifman, N. (2021). Sex and APOE Genotype Differences Related to Statin Use in The Aging Population. Alzheimer's & Dementia, 7(1). doi:10.1002/trc2.12156
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  Significant evidence suggests that the cholesterol-lowering statins can affect cognitive function and reduce the risk for Alzheimer's disease (AD) and dementia. These potential effects may be constrained by specific combinations of an individual's sex and apolipoprotein E (APOE) genotype.
• Brinton, R. D., Dagliati, A., Peek, N., & Geifman, N. (2021). Sex and APOE Genotype Differences Related to Statin Use in The Aging Population. Alzheimers & Dementia, 7(1). doi:10.1002/trc2.12156
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   Significant evidence suggests that the cholesterol-lowering statins can affect cognitive function and reduce the risk for Alzheimer's disease (AD) and dementia. These potential effects may be constrained by specific combinations of an individual's sex and apolipoprotein E (APOE) genotype.
• Brinton, R., Mosconi, L., Berti, V., Dyke, J., Schelbaum, E., Jett, S., Laughlin, L., Jang, G., Rahman, A., Hristov, H., Pahlajani, S., Andrews, R., Matthews, D., Etingin, O., Ganzer, C., Leon, M. d., & Isaacson, R. (2021). Menopause Impacts Human Brain Structure, Connectivity, Energy Metabolism, and Amyloid-beta Deposition.. Scientific Reports, 11(1). doi:10.1038/s41598-021-90084-y
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  All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer's disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.
• Brinton, R., Mosconi, L., Berti, V., Dyke, J., Schelbaum, E., Jett, S., Laughlin, L., Jang, G., Rahman, A., Hristov, H., Pahlajani, S., Andrews, R., Matthews, D., Etingin, O., Ganzer, C., Leon, M. d., & Isaacson, R. (2021). Menopause Impacts Human Brain Structure, Connectivity, Energy Metabolism, and Amyloid-beta Deposition.. Scientific Reports, 11(10867). doi:10.1038/s41598-021-90084-y
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  All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer's disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.     
• Haro, G. T., Branigan, G., Vitali, F., & Brinton, R. D. (2021). Statin Therapy and Risk of Alzheimer’s and Age-related Neurodegenerative Diseases. Neurology, 96(15_supplement). doi:10.1212/wnl.96.15_supplement.4074
• Kim, Y. J., & Brinton, R. D. (2021). Precision hormone therapy: identification of positive responders.. Climacteric : the journal of the International Menopause Society, 24(4), 350-358. doi:10.1080/13697137.2021.1882418
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  Since the introduction of menopausal hormone therapy (MHT) in the 1940s, randomized clinical trials and observational studies have been performed to determine the benefits and risks of MHT. However, MHT therapeutic impact remains under debate as multiple factors including genetic biomarkers and medical history contribute to inter-individual variations in neurodegenerative diseases. Herein, we review the characteristics of women who participated in clinical studies and methodological approaches for study analyses to assess the critical variables influencing an association between MHT and risk of neurodegenerative diseases. Outcomes of the review indicated that: (1) observational studies assessed outcomes of MHT in symptomatic women whereas MHT clinical trials were conducted in asymptomatic postmenopausal women not treated for menopausal symptoms, (2) in asymptomatic postmenopausal women, late MHT intervention was of no benefit, (3) different MHT treatments and regimens between observational studies and clinical trials may impact outcomes, and (4) observational studies may provide greater predictive validity for long-term neurological health outcomes as MHT was introduced in symptomatic women and administered over a long period of time. Going forward, achieving precision hormone therapy will require a priori identification of symptomatic women appropriate for MHT and the type and dose of MHT appropriate for their genetic profile and health risks.
• Mosconi, L., Berti, V., Dyke, J., Schelbaum, E., Jett, S., Loughlin, L., Jang, G., Rahman, A., Hristov, H., Pahlajani, S., Andrews, R., Matthews, D., Etingin, O., Ganzer, C., de Leon, M., Isaacson, R., & Brinton, R. D. (2021). Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition. Scientific reports, 11(1), 10867. doi:10.1038/s41598-021-90084-y
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  All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer's disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.
• Peek, N., Geifman, N., Dagliati, A., & Brinton, R. D. (2021). Sex and APOE genotype differences related to statin use in the aging population. Alzheimer's & Dementia: Translational Research & Clinical Interventions. doi:10.1002/trc2.12156
• Peek, N., Geifman, N., Dagliati, A., & Brinton, R. D. (2021). Sex and APOE genotype differences related to statin use in the aging population.. Alzheimer's & dementia (New York, N. Y.), 7(1), e12156. doi:10.1002/trc2.12156
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  Significant evidence suggests that the cholesterol-lowering statins can affect cognitive function and reduce the risk for Alzheimer's disease (AD) and dementia. These potential effects may be constrained by specific combinations of an individual's sex and apolipoprotein E (APOE) genotype..Here we examine data from 252,327 UK Biobank participants, aged 55 or over, and compare the effects of statin use in males and females. We assessed difference in statin treatments taking a matched cohort approach, and identified key stratifiers using regression models and conditional inference trees. Using statistical modeling, we further evaluated the effect of statins on survival, cognitive decline over time, and on AD prevalence..We identified that in the selected population, males were older, had a higher level of education, better cognitive scores, higher incidence of cardiovascular and metabolic diseases, and a higher rate of statin use. We observed that males and those participants with an APOE ε4-positive genotype had higher probabilities of being treated with statins; while participants with an AD diagnosis had slightly lower probabilities. We found that use of statins was not significantly associated with overall higher rates of survival. However, when considering the interaction of statin use with sex, the results suggest higher survival rates in males treated with statins. Finally, examination of cognitive function indicates a potential beneficial effect of statins that is selective for APOE ε4-positive genotypes..Our evaluation of the aging population in a large cohort from the UK Biobank confirms sex and APOE genotype as fundamental risk stratifiers for AD and cognitive function, furthermore it extends them to the specific area of statin use, clarifying their specific interactions with treatments.
• Schelbaum, E., Loughlin, L., Jett, S., Zhang, C., Jang, G., Malviya, N., Hristov, H., Pahlajani, S., Isaacson, R., Dyke, J. P., Kamel, H., Brinton, R. D., & Mosconi, L. (2021). Association of Reproductive History With Brain MRI Biomarkers of Dementia Risk in Midlife. Neurology, 97(23), e2328-e2339.
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  To examine associations between indicators of estrogen exposure from women's reproductive history and brain MRI biomarkers of Alzheimer disease (AD) in midlife.
• Soto, M., Rodgers, K. E., Kim, Y. J., Brinton, R. D., & Branigan, G. L. (2021). Association between menopausal hormone therapy and risk of neurodegenerative diseases: Implications for precision hormone therapy.. Alzheimer's & dementia (New York, N. Y.), 7(1), e12174. doi:10.1002/trc2.12174
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  The impact of menopausal hormone therapy (HT) on age-associated Alzheimer's and neurodegenerative diseases (NDDs) remains unresolved. To determine the effect of HT, formulation, type, and duration on risk of NDDs, a retrospective analysis was performed using a 10-year Humana claims dataset..Study population included women aged 45 years or older with or without claim records of HT medications. Patients diagnosed with NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), dementia, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) were identified. Relative risk (RR) ratios and 95% confidence intervals (CI) for combined NDDs, or AD, PD, dementia, MS, and ALS were determined. Cumulative hazard ratios were determined to investigate the association between HT and NDDs at different age groups..In 379,352 women with or without claim records of HT, use of HT was associated with significantly reduced risk for combined NDDs (RR 0.42, 95% CI 0.40-0.43, P < 0.001). Average follow-up time was 5.1 [2.3] years. Formulations containing natural steroids 17β-estradiol and/or progesterone were associated with greater reduction in NDD risk. Oral- HT users showed significantly reduced RRs (0.42, 0.41-0.44, P < 0.001) for combined NDDs compared to non-HT users. The RRs for transdermal-HT users were significantly decreased for all-cause dementia (0.73, 0.60-0.88, P = 0.001) and MS (0.55, 0.36-0.84, P = 0.005). Greatest reduction in risk of NDD, AD, and dementia emerged in patients aged 65 years or older. Further, the protective effect of long-term therapy (>1 year) on combined NDDs, AD, PD, and dementia was greater compared to short-term therapy (≤1 year)..HT was associated with reduced risk of all NDDs including AD and dementia, with greater duration of therapy and natural steroid formulations associated with greater efficacy. These findings advance precision HT to prevent NDDs including AD.
• Soto, M., Rodgers, K. E., Mishra, A., Delatorre, N., & Brinton, R. D. (2021). APOE4 genetic burden and female sex impact immune profile in brain and periphery in aged mice.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 3, e056541. doi:10.1002/alz.056541
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  APOE4 isoform and female sex are genetic risk factors for Alzheimer's disease (AD) with women APOE4 carriers being at greater and accelerated risk for developing AD than men. Inflammation contributes to the AD disease progression. Apolipoprotein E (ApoE), and endocrine aging in women are known to impact antigen presentation, microglial function, T cell activation and the systemic inflammatory profile. We hypothesize that the interaction of female sex and APOE4 isoform exacerbates inflammation and thereby be evident in microglial reactivity, loss of function and peripheral immune cell activation contributing to the at-risk AD profile..18-month-old Humanized (h)APOE3/3, APOE3/4 and APOE4/4 male and female mice from the Jackson labs were used. Single cell suspension generated from blood, spleen and brain were analyzed using flow cytometry. In the brain, microglial phagocytosis, cellular reactive oxygen species (ROS) production, MHC-II expression and lipid droplet accumulation was measured. T cell infiltration in the brain was also established. Additionally, metabolic flux assays on microglial cells. In the periphery, CD4 and CD8 T cell populations and T cell activation were quantified..In the brain, microglia from hAPOE4/4 females had the highest expression of MHC-II and significantly lower phagocytic activity in comparison to hAPOE4/4 males and hAPOE3/3 females. Coincident with increased microglial reactivity, significantly higher T cells were detected in hAPOE4/4 female brain in comparison to hAPOE3/3 males. Interestingly, neutral lipid droplet accumulation was significantly higher in hAPOE3/3 females in comparison to hAPOE3/4 females consistent with a profile of increased phagocytic activity. Peripheral immune profile from the blood and spleen indicated patterns consistent with the brain-immune analyses. APOE4 genotype had a significant impact on the proportion of activated CD4 and CD8 T cells. Female hAPOE4/4 had significantly higher CD4+CD69+ and CD8+CD69+ T cells in comparison to hAPOE3/3 and hAPOE3/4 females in blood. In spleen, females across all the genotype had greater proportions of activated T cells, of which female hAPOE4/4 had the highest proportions of activated CD4 and CD8 T cells..The interaction of APOE4 genotype and sex affects the immune profile in the brain and periphery which is consistent with accelerated generation of at-risk for AD immune profile.
• Talboom, J. S., De Both, M. D., Naymik, M. A., Schmidt, A. M., Lewis, C. R., Jepsen, W. M., Håberg, A. K., Rundek, T., Levin, B. E., Hoscheidt, S., Bolla, Y., Brinton, R. D., Schork, N. J., Hay, M., Barnes, C. A., Glisky, E., Ryan, L., & Huentelman, M. J. (2021). Two separate, large cohorts reveal potential modifiers of age-associated variation in visual reaction time performance. NPJ aging and mechanisms of disease, 7(1), 14. doi:10.1038/s41514-021-00067-6
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  To identify potential factors influencing age-related cognitive decline and disease, we created MindCrowd. MindCrowd is a cross-sectional web-based assessment of simple visual (sv) reaction time (RT) and paired-associate learning (PAL). svRT and PAL results were combined with 22 survey questions. Analysis of svRT revealed education and stroke as potential modifiers of changes in processing speed and memory from younger to older ages (n = 75,666, n = 47,700, n = 27,966; ages 18-85 years old, mean (M) = 46.54, standard deviation (SD) = 18.40). To complement this work, we evaluated complex visual recognition reaction time (cvrRT) in the UK Biobank (n = 158,249 n = 89,333 n = 68,916; ages 40-70 years old, M = 55.81, SD = 7.72). Similarities between the UK Biobank and MindCrowd were assessed using a subset of MindCrowd (UKBb MindCrowd) selected to mirror the UK Biobank demographics (n = 39,795, n = 29,640, n = 10,155; ages 40-70 years old, M = 56.59, SD = 8.16). An identical linear model (LM) was used to assess both cohorts. Analyses revealed similarities between MindCrowd and the UK Biobank across most results. Divergent findings from the UK Biobank included (1) a first-degree family history of Alzheimer's disease (FHAD) was associated with longer cvrRT. (2) Men with the least education were associated with longer cvrRTs comparable to women across all educational attainment levels. Divergent findings from UKBb MindCrowd included more education being associated with shorter svRTs and a history of smoking with longer svRTs from younger to older ages.
• Talboom, J. S., Schmidt, A. M., Ryan, L., Rundek, T., Naymik, M. A., Lewis, C. R., Levin, B. E., Huentelman, M. J., Hoscheidt, S. M., Hay, M., Haberg, A. K., Glisky, E. L., Brinton, R. D., Both, M. D., Bolla, Y., & Barnes, C. A. (2021). Smoking is associated with impaired verbal learning and memory performance in women more than men.. Scientific reports, 11(1), 10248. doi:10.1038/s41598-021-88923-z
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  Vascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase the likelihood of cognitive impairment by exacerbating vascular disease risks. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific relationships between smoking and memory performance and with contradictory results. We investigated the associations between sex, smoking, and cardiovascular disease with verbal learning and memory function. Using MindCrowd, an observational web-based cohort of ~ 70,000 people aged 18-85, we investigated whether sex modifies the relationship between smoking and cardiovascular disease with verbal memory performance. We found significant interactions in that smoking is associated with verbal learning performance more in women and cardiovascular disease more in men across a wide age range. These results suggest that smoking and cardiovascular disease may impact verbal learning and memory throughout adulthood differently for men and women.
• Torrandell-haro, G., Brinton, R. D., & Branigan, G. L. (2021). Breast cancer therapies reduce risk of Alzheimer’s disease and dementia: A claims‐based retrospective study with clinic to bench implications. Alzheimer's & Dementia, 17(S10). doi:10.1002/alz.055602
• Torrandell-haro, G., Brinton, R. D., & Branigan, G. L. (2021). Individual classes of prostate cancer therapies impact risk of Alzheimer’s disease: A claims‐based retrospective study. Alzheimer's & Dementia, 17(S10), e055615. doi:10.1002/alz.055615
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  Prostate cancer is the most prevalent non-skin cancer in men and the second leading cause of cancer related deaths among men worldwide. There are growing concerns regarding a potential association between androgen targeting therapeutic exposure and Alzheimer’s disease (AD) where the existent literature is limited and highly controversial. The object of this study was to determine whether androgen targeting therapy (ATT) exposure is associated with risk of Alzheimer’s (AD) in men with prostate cancer in the Symphony claims data set.
• Vitali, F., Branigan, G. L., & Brinton, R. D. (2021). Preventing Alzheimer's disease within reach by 2025: Targeted-risk-AD-prevention (TRAP) strategy. Alzheimer's & dementia (New York, N. Y.), 7(1), e12190. doi:10.1002/trc2.12190
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  Alzheimer's disease (AD) is a progressive neurodegenerative disease that currently affects 6.2 million people in the United States and is projected to impact 12.7 million worldwide in 2050 with no effective disease-modifying therapeutic or cure. In 2011 as part of the National Alzheimer's Project Act, the National Plan to Address Alzheimer's Disease was signed into law which proposed to effectively prevent AD by 2025, which is rapidly approaching. The preclinical phase of AD can begin 20 years prior to diagnosis, which provides an extended window for preventive measures that would exert a transformative impact on incidence and prevalence of AD.
• Vitali, F., Brinton, R. D., & Branigan, G. L. (2021). Preventing Alzheimer’s disease within reach by 2025: Targeted-risk-AD-prevention (TRAP) strategy. Alzheimer's & Dementia, 17(S10). doi:10.1002/trc2.12190
• Vitali, F., Torrandell-haro, G., Brinton, R. D., & Branigan, G. L. (2021). Statin therapies reduce risk of Alzheimer’s disease and dementia with increased protective therapeutic effect with increasing age. Alzheimer's & Dementia, 17(S10). doi:10.1002/alz.055735
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  A previous peer-reviewed publication (Torrandell-Haro et al. 2020, Alzheimer’s & Dementia: TRCI) reported that statin therapy was associated with risk reduction of Alzheimer’s disease. Herein we sought to determine the replication validity of statin therapy on the incidence of Alzheimer’s disease and dementia in a larger dataset with a clinical population of 15 million participants.
• Wang, T., Shang, Y., Mao, Z., Chen, S., & Brinton, R. D. (2021). Allopregnanolone potentiates bioenergetic capacity and mitochondrial biogenesis in astrocytes.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 3, e056456. doi:10.1002/alz.056456
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  We reported previously that the neurosteroid allopregnanolone (Allo) promotes neural stem cell regeneration and differentiation, reverses neurogenic, metabolic and cognitive deficits and reduces Alzheimer's disease (AD) pathology in a mouse model of AD. To further investigate the cell-type specific mechanisms of Allo in regulating brain energy metabolism, we assessed the effect of Allo on mitochondrial bioenergetic profile and biogenesis in rat hippocampal astrocytes..E18 rat hippocampal astrocyte were cultured for 10 days in DMEM:F12(1:1) with 10% FBS and then starved in 10% Charcoal stripped-FBS / DMEM:F12 for 24 hours before treatment with 100nM Allo or 0.001% Vehicle overnight. Upon completion of treatment, cells were subject to morphological, biochemical, metabolic and transcriptomic characterization of their mitochondrial phenotypes..In primary hippocampal astrocytes, Allo significantly attenuates serum deprivation-induced bioenergetic deficits and oxidative stress by enhancing mitochondrial biogenesis and rebalancing mitochondrial dynamics. Allo treatment significantly enhances astrocytic mitochondrial biogenesis via Nrf1/Tfam signaling and reverses mitochondrial hyperfusion by elevating the ratio of mitochondrial fission protein Drp1 to the fusion protein Opa1. Functionally, Allo-induced improvement in bioenergetic function is coupled with reduced inflammasome activation in astrocytes..Outcomes of our findings further support the promising therapeutic effects of Allo against bioenergetic deficits that emerge in early phases of AD, with mitochondria being a major effector.
• Yin, F., Yin, F., Qi, G., Mi, Y., & Brinton, R. D. (2021). Mitochondria-Targeted Therapeutics for Alzheimer's Disease: The Good, the Bad, the Potential.. Antioxidants & redox signaling, 34(8), 611-630. doi:10.1089/ars.2020.8070
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  Significance: Alzheimer's disease (AD) is the leading cause of dementia. Thus far, 99.6% of clinical trials, including those targeting energy metabolism, have failed to exert disease-modifying efficacy. Altered mitochondrial function and disruption to the brain bioenergetic system have long-been documented as early events during the pathological progression of AD. Recent Advances: While therapeutic approaches that directly promote mitochondrial bioenergetic machinery or eliminate reactive oxygen species have exhibited limited translatability, emerging strategies targeting nonenergetic aspects of mitochondria provide novel therapeutic targets with the potential to modify AD risk and progression. Growing evidence also reveals a critical link between mitochondrial phenotype and neuroinflammation via metabolic reprogramming of glial cells. Critical Issues: Herein, we summarize major classes of mitochondrion-centered AD therapeutic strategies. In addition, the discrepancy in their efficacy when translated from preclinical models to clinical trials is addressed. Key factors that differentiate the responsiveness to bioenergetic interventions, including sex, apolipoprotein E genotype, and cellular diversity in the brain, are discussed. Future Directions: We propose that the future development of mitochondria-targeted AD therapeutics should consider the interactions between bioenergetics and other disease mechanisms, which may require cell-type-specific targeting to distinguish neurons and non-neuronal cells. Moreover, a successful strategy will likely include stratification by metabolic phenotype, which varies by sex and genetic risk profile and dynamically changes throughout the course of disease. As the network of mitochondrial integration expands across intracellular and systems level biology, assessment of intended, the good, versus unintended consequences, the bad, will be required to reach the potential of mitochondrial therapeutics.
• Yin, F., Yin, F., Shi, X., Qi, G., Mi, Y., Gu, H., & Brinton, R. D. (2021). ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism.. Cell reports, 34(1), 108572. doi:10.1016/j.celrep.2020.108572
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  Alzheimer's disease (AD) risk gene ApoE4 perturbs brain lipid homeostasis and energy transduction. However, the cell-type-specific mechanism of ApoE4 in modulating brain lipid metabolism is unclear. Here, we describe a detrimental role of ApoE4 in regulating fatty acid (FA) metabolism across neuron and astrocyte in tandem with their distinctive mitochondrial phenotypes. ApoE4 disrupts neuronal function by decreasing FA sequestering in lipid droplets (LDs). FAs in neuronal LDs are exported and internalized by astrocytes, with ApoE4 diminishing the transport efficiency. Further, ApoE4 lowers FA oxidation and leads to lipid accumulation in both astrocyte and the hippocampus. Importantly, diminished capacity of ApoE4 astrocytes in eliminating neuronal lipids and degrading FAs accounts for their compromised metabolic and synaptic support to neurons. Collectively, our findings reveal a mechanism of ApoE4 disruption to brain FA and bioenergetic homeostasis that could underlie the accelerated lipid dysregulation and energy deficits and increased AD risk for ApoE4 carriers.
• Zhang, H., Sitruk-ware, R., Sheyner, M., Shear, A., Schumacher, M., Sadanandan, N., Nicola, A. F., Navarro, L., Lee, J., Kumar, N., Heyck, M., Gonzales-portillo, B., Garcia-sanchez, J., El-etr, M., Corey, S., Coats, A. B., Castelli, V., Brinton, R. D., Borlongan, C. V., , Bonsack, B., et al. (2021). Progress in progestin-based therapies for neurological disorders.. Neuroscience and biobehavioral reviews, 122, 38-65. doi:10.1016/j.neubiorev.2020.12.007
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  Hormone therapy, primarily progesterone and progestins, for central nervous system (CNS) disorders represents an emerging field of regenerative medicine. Following a failed clinical trial of progesterone for traumatic brain injury treatment, attention has shifted to the progestin Nestorone for its ability to potently and selectively transactivate progesterone receptors at relatively low doses, resulting in robust neurogenetic, remyelinating, and anti-inflammatory effects. That CNS disorders, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), and stroke, develop via demyelinating, cell death, and/or inflammatory pathological pathways advances Nestorone as an auspicious candidate for these disorders. Here, we assess the scientific and clinical progress over decades of research into progesterone, progestins, and Nestorone as neuroprotective agents in MS, ALS, SCI, and stroke. We also offer recommendations for optimizing timing, dosage, and route of the drug regimen, and identifying candidate patient populations, in advancing Nestorone to the clinic.
• Zissimopoulos, J., Thunell, J., Shekelle, P. G., Joyce, G. F., Chen, Y., Brinton, R. D., & Barthold, D. (2021). Drug therapies for chronic conditions and risk of Alzheimer's disease and related dementias: A scoping review.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 17(1), 41-48. doi:10.1002/alz.12175
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  Most older Americans use drug therapies for chronic conditions. Several are associated with risk of Alzheimer's disease and related dementias (ADRD)..A scoping review was used to identify drug classes associated with increasing or decreasing ADRD risk. We analyzed size, type, and findings of the evidence..We identified 29 drug classes across 11 therapeutic areas, and 404 human studies. Most common were studies on drugs for hypertension (93) or hyperlipidemia (81). Fewer than five studies were identified for several anti-diabetic and anti-inflammatory drugs. Evidence was observational only for beta blockers, proton pump inhibitors, benzodiazepines, and disease-modifying anti-rheumatic drugs. For 13 drug classes, 50% or more of the studies reported consistent direction of effect on risk of ADRD..Future research targeting drug classes with limited/non-robust evidence, examining sex, racial heterogeneity, and separating classes by molecule, will facilitate understanding of associated risk, and inform clinical and policy efforts to alleviate the growing impact of ADRD.
• Albert, M., Brinton, R. D., Cable, J., Holtzman, D. M., Hyman, B. T., Tansey, M. G., Colonna, M., Kellis, M., Wellington, C. L., Sisodia, S. S., & Tanzi, R. E. (2020). Alternatives to amyloid for Alzheimer's disease therapies—a symposium report. Annals of the New York Academy of Sciences, 1475(1), 3-14. doi:10.1111/nyas.14371
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  For decades, Alzheimer's disease research has focused on amyloid as the primary pathogenic agent. This focus has driven the development of numerous amyloid-targeting therapies; however, with one possible exception, none of these therapies have been effective in preventing or delaying cognitive decline in patients, and there are no approved disease-modifying agents. It is becoming more apparent that alternative drug targets are needed to address this complex disease. An increased understanding of Alzheimer's disease pathology has highlighted the need to target the appropriate disease pathology at the appropriate time in the disease course. Preclinical and early clinical studies have focused on targets, including inflammation, tau, vascular health, and the microbiome. This report summarizes the presentations from a New York Academy of Sciences' one-day symposium entitled "Alzheimer's Disease Therapeutics: Alternatives to Amyloid," held on November 20, 2019.
• Bengtsson, S. K., Backstrom, T., Irwin, R. W., Johansson, M., Sjostedt, J., Wang, W., Wang, M. D., & Brinton, R. D. (2020). GABA-A receptor modulating steroids in acute and chronic stress; relevance for cognition and dementia?. Neurobiology of stress, 12, 100206. doi:10.1016/j.ynstr.2019.100206
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  Cognitive dysfunction, dementia and Alzheimer's disease (AD) are increasing as the population worldwide ages. Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A receptor modulating steroid allopregnanolone (APα), it's role in underlying mechanisms for impaired cognition and of AD, and to determine options for therapy of AD. On one hand, APα given intermittently promotes neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of APα impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups to analyze the mechanisms underlying the difference. We conclude that the effects of APα depend on administration pattern and that chronic slightly increased APα exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pathology. These collaborative assessments provide insights for the therapeutic development of APα and APα antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials.
• Brinton, R. (2020). Allopregnanolone Promotes Neuroonal and Oligodendrocyte Differentiation In Vitro and In Vivo: Therapeutic Implication for Alzheimer’s Disease. Neurotherapeutics.
• Brinton, R. (2020). Alternatives to Amyloid for Alzheimer’s Disease Therapies – A Symposium Report. Ann NY Acad Sci.
• Brinton, R. (2020). Association Between Hormone-Modulating Breast Cancer Therapies and Incidence of Neurodegenerative Outcomes for Women With Breast Cancer. JAMA Netw Open.
• Brinton, R. (2020). Association of hot flushes with ghrelin and adipokines in early versus late postmenopausal women. Menopause.
• Brinton, R. (2020). Brain Energy Rescue: An Emerging Therapeutic Concept for Neurodegenerative Disorders of Ageing. Nat Rev Drug Discov.
• Brinton, R. (2020). Dynamic Neuroimmune Profile during Mid-life Aging in the Female Brain and Implications for Alzheimer Risk. iScience.
• Brinton, R. (2020). Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice. PLoS ONE.
• Brinton, R. (2020). Hypertension and Age-Related Cognitive Impairment: Common Risk Factors and a Role for Precision Aging. Curr Hypertens Rep.
• Brinton, R. (2020). Mitochondria Targeted Therapeutics for Alzheimer's Disease: The Good. The Bad. The Potential. Antioxid Redrox Signal.
• Brinton, R. (2020). Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer’s disease: A single and multiple ascending dose phase 1b/2a clinical trial. Alzheimers Dement.
• Brinton, R. (2020). Sex and APOE Genotype Differences Related to Statin Use in The Aging Population. Alzheimer's and Dementia, 7(1). doi:10.21203/rs.3.rs-70804/v1
• Brinton, R. (2020). Sex and APOE ε4 genotype modify the Alzheimer's disease serum metabolome. Nat Commun.
• Brinton, R. (2020). Sex and Gender: Modifiers of Health, Disease and Medicine. Lancet.
• Brinton, R. (2020). Sex-driven Modifiers of Alzheimer Risk: A Multimodality Brain Imaging Study. Neurology.
• Brinton, R. (2020). Statin therapy and risk of Alzheimer’s and age-related neurodegenerative diseases. Alzheimers Dement.
• Brinton, R. (2020). Transitions in metabolic and immune systems from pre-menopause to post-menopause: implications for age-associated neurodegenerative diseases. F1000Res.
• Brinton, R. D., Rodgers, K. E., Hernandez, G. D., Solinsky, C. M., Mack, W. J., Kono, N., Wu, C., Mollo, A. R., Lopez, C. M., Pawluczyk, S., Bauer, G., Matthews, D., Shi, Y., Law, M., Rogawski, M. A., & Schneider, L. S. (2020). Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial. Alzheimer's & Dementia, 6(1). doi:10.1002/trc2.12107
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  Allopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well‐established preclinical safety efficacy make it a viable candidate.
• Hoscheidt, S. M., Yassine, H. N., Pi-sunyer, X., Peters, A. L., Keller, J. N., Hugenschmidt, C. E., Hoscheidt, S. M., Espeland, M. A., Carmichael, O., Brinton, R. D., & Anderson, A. (2020). Do menopausal status and APOE4 genotype alter the long-term effects of intensive lifestyle intervention on cognitive function in women with type 2 diabetes mellitus?. Neurobiology of aging, 92, 61-72. doi:10.1016/j.neurobiolaging.2020.03.020
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  In the Look AHEAD trial, randomization to Intensive Lifestyle Intervention (ILI) or Diabetes Support and Education (DSE) did not result in differences in cognitive outcomes. However, menopause and APOE genotype are factors that affect the response to this intervention. The effect of this intervention on a single cognitive assessment was examined in 3 groups of women: premenopausal or
• Hoscheidt, S. M., Yassine, H. N., Yasar, S., Neiberg, R. H., Luchsinger, J. A., Lockhart, S. N., Hoscheidt, S. M., Hayden, K. M., Espeland, M. A., Carmichael, O., & Brinton, R. D. (2020). Sex-Related Differences in Brain Volumes and Cerebral Blood Flow Among Overweight and Obese Adults With Type 2 Diabetes: Exploratory Analyses From the Action for Health in Diabetes Brain Magnetic Resonance Imaging Study.. The journals of gerontology. Series A, Biological sciences and medical sciences, 75(4), 771-778. doi:10.1093/gerona/glz090
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  Sex may be an important modifier of brain health in response to risk factors. We compared brain structure and function of older overweight and obese women and men with type 2 diabetes mellitus..Cross-sectional cognitive assessments and magnetic resonance images were obtained in 224 women and 95 men (mean age 69 years) with histories of type 2 diabetes mellitus and overweight or obesity. Prior to magnetic resonance images, participants had completed an average of 10 years of random assignment to either multidomain intervention targeting weight loss or a control condition of diabetes support and education. Total (summed gray and white) matter volumes, white matter hyperintensity volumes, and cerebral blood flow across five brain regions of interest were analyzed using mixed-effects models..After covariate adjustment, women, compared with men, averaged 10.9 [95% confidence interval 3.3, 18.5; ≈1%] cc greater summed region of interest volumes and 1.39 [0.00002, 2.78; ≈54%] cc greater summed white matter hyperintensity volumes. Sex differences could not be attributed to risk factor profiles or intervention response. Their magnitude did not vary significantly with respect to age, body mass index, intervention assignment, or APOE-ε4 genotype. Sex differences in brain magnetic resonance images outcomes did not account for the better levels of cognitive functioning in women than men..In a large cohort of older overweight or obese adults with type 2 diabetes mellitus, differences in brain volumes and white matter disease were apparent between women and men, but these did not account for a lower prevalence of cognitive impairment in women compared with men in this cohort..NCT00017953.
• Luo, M., Willis, W. T., Mandarino, L. J., Willis, W. T., Wang, T., Sand, Z., Mandarino, L. J., Ma, W., Luo, M., Finlayson, J., & Brinton, R. D. (2020). Von Willebrand factor A domain-containing protein 8 (VWA8) localizes to the matrix side of the inner mitochondrial membrane.. Biochemical and biophysical research communications, 521(1), 158-163. doi:10.1016/j.bbrc.2019.10.095
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  VWA8 is a poorly characterized mitochondrial AAA + ATPase protein. The specific submitochondrial localization of VWA8 remains unclear. The purpose of this study was to determine the specific submitochondrial compartment within which VWA8 resides in order to provide more insight into the function of this protein. Bioinformatics analysis showed that VWA8 has a 34 amino acid N-terminal Matrix-Targeting Signal (MTS) that is similar to those in proteins known to localize to the mitochondrial matrix. Experiments in C2C12 mouse myoblasts using confocal microscopy showed that deletion of the VWA8 MTS (vMTS) resulted in cytosolic, rather than mitochondrial, localization of VWA8. Biochemical analysis using differential sub-fractionation of mitochondria isolated from rat liver showed that VWA8 localizes to the matrix side of inner mitochondrial membrane, similar to the inner mitochondrial membrane protein Electron Transfer Flavoprotein-ubiquinone Oxidoreductase (ETFDH). The results of these experiments show that the vMTS is essential for localization to the mitochondrial matrix and that once there, VWA8 localizes to the matrix side of inner mitochondrial membrane.
• Wershiner, D., Wang, Y., Seyfert-margolis, V., Lopez, C. M., Hernandez, G. D., Gisler, T. D., & Brinton, R. D. (2020). Precision Functional Assessment for Alzheimer’s disease (PFA‐AD): A pilot study framework. Alzheimers & Dementia, 16(S11). doi:10.1002/alz.046289
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  Current clinical trial assessments of cognitive function and activities of daily living are based on periodic assessments conducted under controlled clinical conditions using standardized measures. This approach is highly correlated with diagnosis of Alzheimer’s disease (AD) but has varied relevance to the real-life challenges of those living with the disease and their caregivers. The use of digital technologies in clinical trials is actively encouraged. The opportunity to embed these tools in clinical trials in parallel with traditional measures is needed to move the field forward. This pilot study provides a framework to build on this approach and expand its use in research and patient care management. PFA-AD will enable: 1) identification of key behavioral challenges that are relevant to the person with AD and their caregivers; 2) assessment of therapeutic effect in real time across multiple domains of behavioral function; and 3) innovate clinical trial measures of daily activities that are personalized and relevant to the patient and caregiver.
• Woolley, C. S., Shansky, R. M., Lupien, S. J., Gould, E., Galea, L. A., Conrad, C. D., Cameron, H. A., & Brinton, R. D. (2020). A Tribute to Bruce S. McEwen. Trends in Neurosciences, 43(3), 127-130. doi:10.1016/j.tins.2020.01.006
• Yao, J., Wang, T., Mao, Z., Chen, S., & Brinton, R. D. (2020). Allopregnanolone Reverses Bioenergetic Deficits in Female Triple Transgenic Alzheimer's Mouse Model.. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 17(1), 178-188. doi:10.1007/s13311-019-00793-6
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  Previously, we reported that the neurosteroid allopregnanolone (Allo) promoted neural stem cell regeneration, restored cognitive function, and reduced Alzheimer's Disease (AD) pathology in the triple transgenic Alzheimer's mouse model (3xTgAD). To investigate the underlying systems biology of Allo action in AD models in vivo, we assessed the regulation of Allo on the bioenergetic system of the brain. Outcomes of these analysis indicated that Allo significantly reversed deficits in mitochondrial respiration and biogenesis and key mitochondrial enzyme activity and reduced lipid peroxidation in the 3xTgAD mice in vivo. To explore the mechanisms by which Allo regulates the brain metabolism, we conducted targeted transcriptome analysis. These data further confirmed that Allo upregulated genes involved in glucose metabolism, mitochondrial bioenergetics, and signaling pathways while simultaneously downregulating genes involved in Alzheimer's pathology, fatty acid metabolism, and mitochondrial uncoupling and dynamics. Upstream regulatory pathway analysis predicted that Allo induced peroxisome proliferator-activated receptor gamma (PPARG) and coactivator 1-alpha (PPARGC1A) pathways while simultaneously inhibiting the presenilin 1 (PSEN 1), phosphatase and tensin homolog (PTEN), and tumor necrosis factor (TNF) pathways to reduce AD pathology. Collectively, these data indicate that Allo functions as a systems biology regulator of bioenergetics, cholesterol homeostasis, and β-amyloid reduction in the brain. These systems are critical to neurological health, thus providing a plausible mechanistic rationale for Allo as a therapeutic to promote neural cell function and reduce the burden of AD pathology.
• Yin, F., Wang, Y., Shang, Y., Mishra, A., Brinton, R. D., & Bacon, E. R. (2020). Midlife Chronological and Endocrinological Transitions in Brain Metabolism: System Biology Basis for Increased Alzheimer's Risk in Female Brain.. Scientific reports, 10(1), 8528. doi:10.1038/s41598-020-65402-5
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  Decline in brain glucose metabolism is a hallmark of late-onset Alzheimer's disease (LOAD). Comprehensive understanding of the dynamic metabolic aging process in brain can provide insights into windows of opportunities to promote healthy brain aging. Chronological and endocrinological aging are associated with brain glucose hypometabolism and mitochondrial adaptations in female brain. Using a rat model recapitulating fundamental features of the human menopausal transition, results of transcriptomic analysis revealed stage-specific shifts in bioenergetic systems of biology that were paralleled by bioenergetic dysregulation in midlife aging female brain. Transcriptomic profiles were predictive of outcomes from unbiased, discovery-based metabolomic and lipidomic analyses, which revealed a dynamic adaptation of the aging female brain from glucose centric to utilization of auxiliary fuel sources that included amino acids, fatty acids, lipids, and ketone bodies. Coupling between brain and peripheral metabolic systems was dynamic and shifted from uncoupled to coupled under metabolic stress. Collectively, these data provide a detailed profile across transcriptomic and metabolomic systems underlying bioenergetic function in brain and its relationship to peripheral metabolic responses. Mechanistically, these data provide insights into the complex dynamics of chronological and endocrinological bioenergetic aging in female brain. Translationally, these findings are predictive of initiation of the prodromal / preclinical phase of LOAD for women in midlife and highlight therapeutic windows of opportunity to reduce the risk of late-onset Alzheimer's disease.
• Yin, F., Wang, Y., Shang, Y., Mishra, A., Brinton, R. D., & Bacon, E. R. (2020). Midlife Chronological and Endocrinological Transitions in Brain Metabolism: System Biology Basis for Increased Alzheimer's Risk in Female Brain.. Scientific Reports, 10(1). doi:10.1038/s41598-020-65402-5
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  Decline in brain glucose metabolism is a hallmark of late-onset Alzheimer's disease (LOAD). Comprehensive understanding of the dynamic metabolic aging process in brain can provide insights into windows of opportunities to promote healthy brain aging. Chronological and endocrinological aging are associated with brain glucose hypometabolism and mitochondrial adaptations in female brain. Using a rat model recapitulating fundamental features of the human menopausal transition, results of transcriptomic analysis revealed stage-specific shifts in bioenergetic systems of biology that were paralleled by bioenergetic dysregulation in midlife aging female brain. Transcriptomic profiles were predictive of outcomes from unbiased, discovery-based metabolomic and lipidomic analyses, which revealed a dynamic adaptation of the aging female brain from glucose centric to utilization of auxiliary fuel sources that included amino acids, fatty acids, lipids, and ketone bodies. Coupling between brain and peripheral metabolic systems was dynamic and shifted from uncoupled to coupled under metabolic stress. Collectively, these data provide a detailed profile across transcriptomic and metabolomic systems underlying bioenergetic function in brain and its relationship to peripheral metabolic responses. Mechanistically, these data provide insights into the complex dynamics of chronological and endocrinological bioenergetic aging in female brain. Translationally, these findings are predictive of initiation of the prodromal / preclinical phase of LOAD for women in midlife and highlight therapeutic windows of opportunity to reduce the risk of late-onset Alzheimer's disease.
• Yin, F., Yin, F., Shi, X., Qi, G., Mi, Y., Gu, H., & Brinton, R. D. (2020). APOE4 impairs neuron-astrocyte coupling of fatty acid metabolism. Alzheimers & Dementia, 16. doi:10.1002/alz.045251
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  Alzheimer's disease (AD) risk gene ApoE4 perturbs brain lipid homeostasis and energy transduction. However, the cell-type-specific mechanism of ApoE4 in modulating brain lipid metabolism is unclear. Here, we describe a detrimental role of ApoE4 in regulating fatty acid (FA) metabolism across neuron and astrocyte in tandem with their distinctive mitochondrial phenotypes. ApoE4 disrupts neuronal function by decreasing FA sequestering in lipid droplets (LDs). FAs in neuronal LDs are exported and internalized by astrocytes, with ApoE4 diminishing the transport efficiency. Further, ApoE4 lowers FA oxidation and leads to lipid accumulation in both astrocyte and the hippocampus. Importantly, diminished capacity of ApoE4 astrocytes in eliminating neuronal lipids and degrading FAs accounts for their compromised metabolic and synaptic support to neurons. Collectively, our findings reveal a mechanism of ApoE4 disruption to brain FA and bioenergetic homeostasis that could underlie the accelerated lipid dysregulation and energy deficits and increased AD risk for ApoE4 carriers.
• Yin, F., Yin, F., Wang, Y., Schneider, L. S., Mack, W. J., Hernandez, G. D., & Brinton, R. D. (2020). Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy.. Menopause (New York, N.Y.), 27(1), 57-65. doi:10.1097/gme.0000000000001418
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  PhytoSERM is a selective estrogen receptor beta (ERβ) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation..In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype..Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response..Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.
• Zissimopoulos, J., Wharton, W., Kehoe, P. G., Joyce, G. F., Brinton, R. D., & Barthold, D. (2020). Association of combination statin and antihypertensive therapy with reduced Alzheimer's disease and related dementia risk.. PloS one, 15(3), e0229541. doi:10.1371/journal.pone.0229541
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  Hyperlipidemia and hypertension are modifiable risk factors for Alzheimer's disease and related dementias (ADRD). Approximately 25% of adults over age 65 use both antihypertensives (AHTs) and statins for these conditions. While a growing body of evidence found statins and AHTs are independently associated with lower ADRD risk, no evidence exists on simultaneous use for different drug class combinations and ADRD risk. Our primary objective was to compare ADRD risk associated with concurrent use of different combinations of statins and antihypertensives..In a retrospective cohort study (2007-2014), we analyzed 694,672 Medicare beneficiaries in the United States (2,017,786 person-years) who concurrently used both statins and AHTs. Using logistic regression adjusting for age, socioeconomic status and comorbidities, we quantified incident ADRD diagnosis associated with concurrent use of different statin molecules (atorvastatin, pravastatin, rosuvastatin, and simvastatin) and AHT drug classes (two renin-angiotensin system (RAS)-acting AHTs, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin-II receptor blockers (ARBs), vs non-RAS-acting AHTs)..Pravastatin or rosuvastatin combined with RAS-acting AHTs reduce risk of ADRD relative to any statin combined with non-RAS-acting AHTs: ACEI+pravastatin odds ratio (OR) = 0.942 (CI: 0.899-0.986, p = 0.011), ACEI+rosuvastatin OR = 0.841 (CI: 0.794-0.892, p
• Brinton, R., & Desai, M. (2019). Automimmune disease in women: Endocrine transition and risk across the lifespan. Front Endocrinol.
• Brinton, R., Bacon, E., Mishra, A., Wang, Y., Desai, M., & Yin, F. (2019). Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation. Neurobiol Aging.
• Brinton, R., Espeland, M., Hayden, K., Lockhart, S., Yassine, H., Horscheidt, S., Yasar, S., Luchsinger, J., Neiberg, R., & Charmichael, O. (2019). Sex-related differences in brain volumes and cerebral blood flow among overweight and obese adults with type 2 diabetes: Exploratory analyses from the action for health in diabetes brain magnetic resonance imaging study. J Gerontol A Biol Sci Med Sci.
• Brinton, R., Karim, R., Mack, W., Sripasert, I., Hodis, H., & Allayee, H. (2019). Effect of ApoE4 Genotype on the Association Between Metabolic Phenotype and Subclinical Atherosclerosis in Postmenopausal Women. Am J Cardiol.
• Brinton, R., Karin, R., Koc, M., Rettberg, J., Hodis, H., Henderson, V., St John, J., Allayee, H., & Mack, W. (2019). Apolipoprotein E4 genotype in combination with poor metabolic profile is associated with reduced cognitive performance in healthy postmenopausal women: implications for late onset Alzheimer’s disease.. Menopause.
• Brinton, R., Luo, M., Ma, W., Sand, Z., Finlayson, J., Wang, T., Willis, W., & Mandarino, L. J. (2019). Von Willebrand factor A domain-containing protein 8 (VWA8) localizes to the matrix side of the inner mitochondrial membrane. Biochem Biophys Res Commun.
• Brinton, R., Rahman, A., Jackson, H., Hristov, H., Issacson, R., Saif, N., Shetty, T., Etingin, O., Henchliffe, C., & Mosconi, L. (2019). Sex and Gender Driven Modifiers of Alzheimer’s: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks. Front Aging Neurosci..
• Brinton, R., Schneider, L., Hernandez, G., Zhao, L., Franke, A., Chen, Y., Pawluczyk, S., & Mack, W. (2019). Safety and feasibility of estrogen receptor-β targeted phytoSERM formulation for menopausal symptoms: phase 1b/2a randomized clinical trial. Menopause.
• Brinton, R., Wang, T., Yao, J., Chen, S., & Mao, J. (2019). Allopregnanolone Reverses Bioenergetic Deficits in Female Triple Transgenic Alzheimer’s Mouse Model. Neurotherapeutics. doi:10.1007/s13311-019-00793-6
• Brinton, R., Wang, Y., Hernandez, G., Mack, W., Schneider, L., & Yin, F. (2019). Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy. Menopause.
• Hoscheidt, S. M., Yassine, H. N., Pi-sunyer, X., Peters, A. L., Keller, J. N., Hugenschmidt, C. E., Hoscheidt, S. M., Espeland, M. A., Carmichael, O. T., Brinton, R. D., & Anderson, A. (2019). P3-038: DO MENOPAUSAL STATUS AND APOE4 GENOTYPE ALTER THE LONG-TERM EFFECTS OF INTENSIVE LIFESTYLE INTERVENTION ON COGNITIVE FUNCTION IN WOMEN WITH TYPE 2 DIABETES MELLITUS?. Alzheimers & Dementia, 15, P940-P940. doi:10.1016/j.jalz.2019.06.3064
• Hoscheidt, S. M., Yassine, H. N., Yasar, S., Neiberg, R. H., Luchsinger, J. A., Lockhart, S. N., Hoscheidt, S. M., Hayden, K. M., Espeland, M. A., Carmichael, O. T., & Brinton, R. D. (2019). IC-P-155: SEX-RELATED DIFFERENCES IN BRAIN VOLUMES AND CEREBRAL BLOOD FLOW AMONG OVERWEIGHT AND OBESE ADULTS WITH TYPE 2 DIABETES. Alzheimers & Dementia, 15(7), P125-P125. doi:10.1016/j.jalz.2019.06.4270
• Shi, Y., Schneider, L. S., Mishra, A., Lopez, C. M., Law, M., Hernandez, G. D., Brinton, R. D., & Aydogan, D. B. (2019). BLOOD-BASED INFLAMMATORY BIOMARKERS FOR PREDICTING THERAPEUTIC RESPONSE IN REGIONAL BRAIN VOLUME CHANGES IN PATIENTS WITH ALZHEIMER’S DISEASE. Alzheimers & Dementia, 15(7), P236. doi:10.1016/j.jalz.2019.06.040
• Wang, T., Mao, Z., Chen, S., & Brinton, R. D. (2019). P3-061: ALLOPREGNANOLONE POTENTIATES BIOENERGETIC CAPACITY AND RESTRUCTURES MITOCHONDRIAL RETICULUM IN NEURONS AND ASTROCYTES. Alzheimers & Dementia, 15, P949-P949. doi:10.1016/j.jalz.2019.06.3088
• Wang, Y., Solinsky, C. M., Schneider, L. S., Hernandez, G. D., & Brinton, R. D. (2019). P3‐032: COMBINING SEX, APOE GENOTYPE, AND MITOCHONDRIAL GENETIC VARIANCE AS PREDICTIVE RESPONDER IDENTIFIER TO REGENERATIVE THERAPEUTIC ALLOPREGNANOLONE FOR ALZHEIMER'S DISEASE. Alzheimers & Dementia, 15, P938-P938. doi:10.1016/j.jalz.2019.06.3058
• Yao, J., Wang, T., Chen, S., & Brinton, R. D. (2019). P3-060: ALLOPREGNANOLONE REVERSED OVARIECTOMY-INDUCED BIOENERGETIC DEFICITS IN FEMALE TRIPLE TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE. Alzheimers & Dementia, 15, P948-P949. doi:10.1016/j.jalz.2019.06.3087
• Yassine, H. N., Yasar, S., Neiberg, R. H., Luchsinger, J. A., Lockhart, S. N., Hoscheidt, S. M., Hayden, K. M., Espeland, M. A., Carmichael, O. T., & Brinton, R. D. (2019). P2-546: SEX-RELATED DIFFERENCES IN BRAIN VOLUMES AND CEREBRAL BLOOD FLOW AMONG OVERWEIGHT AND OBESE ADULTS WITH TYPE 2 DIABETES. Alzheimer's & Dementia, 15, P829-P830. doi:10.1016/j.jalz.2019.06.2954
• Yin, F., Yin, F., Qi, G., Mi, Y., Chen, S., & Brinton, R. D. (2019). P1-195: APOE ISOFORMS DIFFERENTIATE NEURONAL AND ASTROCYTIC MITOCHONDRIAL BIOENERGETIC CAPACITY AND FUEL DEPENDENCY. Alzheimers & Dementia, 15, P311-P312. doi:10.1016/j.jalz.2019.06.750
• Yin, F., Yin, F., Shang, Y., Mao, Z., Lussier, Y. A., Brinton, R. D., & Berghout, J. (2019). P1-202: EMERGENCE OF AN ALZHEIMER'S DISEASE BIOENERGETIC ENDOPHENOTYPE IN MID-LIFE: PRECLINICAL MODEL. Alzheimers & Dementia, 15, P314-P314. doi:10.1016/j.jalz.2019.06.757
• Yin, F., Yin, F., Shang, Y., Schneider, L. S., Lopez, C. M., Hernandez, G. D., & Brinton, R. D. (2019). P3-015: ALLOPREGNANOLONE SHOWS SIGNIFICANT EFFECT ON THE LIPID PATHWAYS FROM PLASMA METABOLOMIC ANALYSIS OF ALZHEIMER'S CLINICAL TRIAL. Alzheimers & Dementia, 15, P930-P930. doi:10.1016/j.jalz.2019.06.3041
• Yin, F., Yin, F., Wang, Y., Shang, Y., Mishra, A., Mao, Z., Desai, M. K., & Brinton, R. D. (2019). P1-194: IMPACT OF APOE GENOTYPE ON THE SEX DIFFERENCES IN BIOENERGETICS AND ALZHEIMER'S RISKS IN THE AGING MOUSE BRAIN. Alzheimers & Dementia, 15, P311-P311. doi:10.1016/j.jalz.2019.06.749
• Zhao, L., Schneider, L. S., Mack, W. J., Hernandez, G. D., & Brinton, R. D. (2019). P2‐027: PHARMACOKINETICS AND SAFETY PROFILE OF SINGLE‐DOSE ADMINISTRATION OF AN ESTROGEN RECEPTOR β‐SELECTIVE PHYTOESTROGENIC (PHYTOSERM) FORMULATION IN WOMEN WITH COGNITIVE DEFICITS AND MENOPAUSAL SYMPTOMS. Alzheimers & Dementia, 15, P581-P582. doi:10.1016/j.jalz.2019.06.1249
• Brinton, R. D., & Mosconi, L. (2018). How would we combat menopause as an Alzheimer’s risk factor?. Expert Review of Neurotherapeutics, 18(9), 689-691. doi:10.1080/14737175.2018.1510320
• Brinton, R., & Mishra, A. (2018). Inflamation: Bridging Age, Menopause and APOEε4 Genotype to Alzheimer’s Disease.. Front. Aging Neurosci.
• Brinton, R., & Mosconi, L. (2018). How would we combat menopause as an Alzheimer’s risk factor?. Expert Rev Neurother.
• Brinton, R., Bacon, E., Mishra, A., Wang, Y., Desai, M., & Yin, F. (2018). Neuroendocrine Aging Precedes Perimenopause and Is Regulated by DNA Methylation.. Neurobiology of Aging.
• Brinton, R., Chen, S., Mao, Z., & Sitruk-Ware, R. (2018). Therapeutic progestin segesterone acetate promotes neurogenesis: implications for sustaining regeneration in female brain.. Menopause.
• Brinton, R., Mosconi, L., Diaz, I., Wu, X., Scheyer, O., Hristov, H., Vallabhajosula, S., Isaacson, R., & de Leon, M. (2018). Increased Alzheimer’s risk during the menopause transition: A 3-year longitudinal brain imaging study. PLoS ONE.
• Prajapati, M., Pirrotte, P., Pathak, K. V., Mcgilvrey, M., Irwin, R. W., Desai, M. K., & Brinton, R. D. (2018). P2-129: ALLOPREGNANOLONE RESTORES COGNITIVE FUNCTION IN APOE4+ FEMALES AND MALES AND PROMOTES METABOLISM OF FUELS REQUIRED FOR ATP GENERATION. Alzheimers & Dementia, 14(7S_Part_13), P717-P718. doi:10.1016/j.jalz.2018.06.815
• Scheyer, O., Rahman, A., Mosconi, L., Isaacson, R. S., Hristov, H., Brinton, R. D., & Berkowitz, C. (2018). Female Sex and Alzheimer's Risk: The Menopause Connection.. The journal of prevention of Alzheimer's disease, 5(4), 225-230. doi:10.14283/jpad.2018.34
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  Along with advanced age and apolipoprotein E (APOE)-4 genotype, female sex is a major risk factor for developing late-onset Alzheimer's disease (AD). Considering that AD pathology begins decades prior to clinical symptoms, the higher risk in women cannot simply be accounted for by their greater longevity as compared to men. Recent investigation into sex-specific pathophysiological mechanisms behind AD risk has implicated the menopause transition (MT), a midlife neuroendocrine transition state unique to females. Commonly characterized as ending in reproductive senescence, many symptoms of MT are neurological, including disruption of estrogen-regulated systems such as thermoregulation, sleep, and circadian rhythms, as well as depression and impairment in multiple cognitive domains. Preclinical studies have shown that, during MT, the estrogen network uncouples from the brain bioenergetic system. The resulting hypometabolic state could serve as the substrate for neurological dysfunction. Indeed, translational brain imaging studies demonstrate that 40-60 year-old perimenopausal and postmenopausal women exhibit an AD-endophenotype characterized by decreased metabolic activity and increased brain amyloid-beta deposition as compared to premenopausal women and to age-matched men. This review discusses the MT as a window of opportunity for therapeutic interventions to compensate for brain bioenergetic crisis and combat the subsequent increased risk for AD in women.
• Schneider, L. S., Rogawski, M. A., Rodgers, K. E., Mack, W. J., Lopez, C. M., Kono, N., Irwin, R. W., Hernandez, G. D., Desai, M. K., & Brinton, R. D. (2018). P1-053: PHARMACOKINETICS AND SAFETY PROFILE OF INTRAVENOUS ADMINISTRATION OF ALLOPREGNANOLONE IN PATIENTS WITH EARLY ALZHEIMER'S DISEASE. Alzheimers & Dementia, 14(7S_Part_5), P288-P288. doi:10.1016/j.jalz.2018.06.055
• Vallabhajosula, S., Swerdlow, R. H., Quinn, C., Pupi, A., Petrongolo, G., Osorio, R. S., Mosconi, L., Mchugh, P., Leon, M. J., Isaacson, R. S., Connaughty, C., Brinton, R. D., & Berti, V. (2018). Correction: Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery.. PloS one, 13(2), e0193314. doi:10.1371/journal.pone.0193314
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  [This corrects the article DOI: 10.1371/journal.pone.0185926.].
• Wang, T., Sitruk-ware, R., Mao, Z., Kumar, N., Chen, S., & Brinton, R. D. (2018). P2-165: THERAPEUTIC PROGESTIN NESTORONE PROMOTES NEUROGENESIS: IMPLICATIONS FOR SUSTAINING REGENERATION IN FEMALE BRAIN. Alzheimers & Dementia, 14(7S_Part_13), P732-P732. doi:10.1016/j.jalz.2018.06.852
• Wang, Y., Solinsky, C. M., Schneider, L. S., Hernandez, G. D., & Brinton, R. D. (2018). P1‐018: MITOCHONDRIAL HAPLOGROUP IN COMBINATION WITH APOE GENOTYPE AS POTENTIAL PREDICTIVE BIOMARKER TO IDENTIFY RESPONDERS TO REGENERATIVE THERAPEUTIC ALLOPREGNANOLONE FOR ALZHEIMER'S DISEASE. Alzheimers & Dementia, 14(7S_Part_4), P271-P272. doi:10.1016/j.jalz.2018.06.019
• Yin, F., Yin, F., Mosconi, L., & Brinton, R. D. (2018). F2‐01‐01: TRANSITIONS OF THE AGING FEMALE BRAIN: WINDOW INTO UNDERLYING MECHANISMS OF LATE ONSET ALZHEIMER'S DISEASE. Alzheimers & Dementia, 14(7S_Part_11), P601-P602. doi:10.1016/j.jalz.2018.06.2611
• Yin, F., Yin, F., Shang, Y., Lussier, Y. A., Brinton, R. D., & Berghout, J. (2018). P3-133: A BIOENERGETIC-INFLAMMATORY TRANSITION STATE CHARACTERIZES PERIMENOPAUSAL AGING BRAIN AND INDICATES ALZHEIMER'S VULNERABILITY. Alzheimers & Dementia, 14(7S_Part_21). doi:10.1016/j.jalz.2018.06.1490
• Yin, F., Yin, F., Trouard, T. P., Shang, Y., Mishra, A., Mao, Z., Do, L., & Brinton, R. D. (2018). P2-204: SEX DIFFERENCES IN METABOLIC AND INFLAMMATORY AGING OF THE BRAIN IN HUMANIZED APOE-ε4 KNOCK-IN RATS. Alzheimers & Dementia, 14(7S_Part_14). doi:10.1016/j.jalz.2018.06.892
• Yin, F., Yin, F., Yao, J., Mao, Z., & Brinton, R. D. (2018). P3-147: RESPONSE TO HORMONAL INTERVENTION IN AGING FEMALE BRAIN IS ENDOCRINE STATUS DEPENDENT: IMPLICATIONS FOR ALZHEIMER'S DISEASE. Alzheimers & Dementia, 14(7S_Part_21), P1124-P1124. doi:10.1016/j.jalz.2018.06.1504
• Brinton, R. D. (2017). FUELING THE GLUCOSE-STARVED ALZHEIMER’S BRAIN: CATABOLISM OF WHITE MATTER IN THE BRAIN TO GENERATE KETONE BODIES. Alzheimers & Dementia, 13(7), P882-P883. doi:10.1016/j.jalz.2017.07.274
• Geifman, N., Brinton, R., Kennedy, R., Schneider, L., & Butte, A. (2017). Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer's disease. Alzheimers Res Ther, 9(1), 10. doi:10.1186/s13195-017-0237-y
• Mosconi, L., Berti, V., Guyara-Quinn, C., McHugh, P., Petrongolo, G., Osorio, R., Connaughty, C., Pupi, A., Vallabhajosula, S., Isaacson, R., deLeon, M., Swerdlow, R., & Brinton, R. (2017). Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery. PLoS One, 12(10). doi:10.1371/journal.pone.0185926
• Mosconi, L., Berti, V., Quinn, C., McHugh, P., Petrongolo, G., Varsavsky, L., Osorio, R., Pupi, A., Vallabhajosula, S., Isaacson, R., deLeon, M., & Brinton, R. (2017). Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging. Neurology, 89(13), 1382-1390. doi:10.1212/WNL.0000000000004425
• Prajapati, M., Irwin, R. W., Desai, M. K., & Brinton, R. D. (2017). APOE AND ALLOPREGNANOLONE: EVALUATING DIFFERENCES IN RESPONSE TO TREATMENT BY GENDER AND GENOTYPE. Alzheimers & Dementia, 13(7), P672-P672. doi:10.1016/j.jalz.2017.06.823
• Schneider, L. S., Law, M., & Brinton, R. D. (2017). ALLOPREGNANOLONE, REGENERATIVE THERAPEUTIC FOR ALZHEIMER’S DISEASE: PHASE 1B/2A UPDATE. Alzheimers & Dementia, 13(7), P939-P940. doi:10.1016/j.jalz.2017.06.1838
• Solinsky, C. M., Park, J. A., Ichida, J. K., Chui, H. C., Brinton, R. D., & Blurton-jones, M. (2017). DEVELOPMENT OF AN IPSC-BASED BIOMARKER STRATEGY TO IDENTIFY NEUROREGENERATIVE RESPONDERS TO ALLOPREGNANOLONE. Alzheimers & Dementia, 13(7), P998-P998. doi:10.1016/j.jalz.2017.06.1379
• Solinsky, C. M., Schneider, L. S., Mack, W. J., Lopez, C. M., Kono, N., Irwin, R. W., Hernandez, G. D., & Brinton, R. D. (2017). CLINICAL TRIAL RECRUITMENT FRAMEWORK FOR EARLY ALZHEIMER’S DISEASE. Alzheimers & Dementia, 13(7), P1262-P1262. doi:10.1016/j.jalz.2017.06.1884
• Wang, J., Trivedi, A., Carrillo, N., Yang, J., Giulivi, C., Adams, P., Tassone, F., Kim, K., Rivera, S., Lubarr, N., Wu, C., Irwin, R., Brinton, R., Olichney, J., Rogawski, M., & Hagerman, R. (2017). Open-Label Allopregnanolone Treatment of Men with Fragile X-Associated Tremor/Ataxia Syndrome. Neurotherapeutics, 14(4), 1073-83. doi:10.1007/s13311-017-0555-6
• Wang, Y., & Brinton, R. D. (2017). ESTROGEN REGULATION OF MITOCHONDRIAL RESPIRATION IS CELL TYPE AND ER SUBTYPE SPECIFIC. Alzheimers & Dementia, 13(7), P665-P666. doi:10.1016/j.jalz.2017.06.801
• Yao, J., Wong, K., Chen, S., & Brinton, R. D. (2017). IMPACT OF ALLOPREGNANOLONE ON NEURAL DIFFERENTIATION: DEVELOPMENT OF A REGENERATIVE THERAPEUTIC FOR ALZHEIMER’S DISEASE. Alzheimers & Dementia, 13(7), P675-P675. doi:10.1016/j.jalz.2017.06.831
• Yin, F., Mishra, A., Mao, Z., & Brinton, R. D. (2017). [P1-210]: SEX DIFFERENCES IN METABOLIC AND NEUROLOGICAL OUTCOMES IN HUMANIZED APOE-ε4 KNOCK-IN RAT MODEL. Alzheimer's & Dementia, 13(7S_Part_6), P323-P323. doi:10.1016/j.jalz.2017.06.030
• Yin, F., Yao, J., Brinton, R., & Cadenas, E. (2017). Editorial: The Metabolic-Inflammatory Axis in Brain Aging and Neurodegeneration. Front Aging Neurosci, 9, 209.
• Yin, F., Yin, F., Mishra, A., Mao, Z., & Brinton, R. D. (2017). SEX DIFFERENCES IN METABOLIC AND NEUROLOGICAL OUTCOMES IN HUMANIZED APOE-ε4 KNOCK-IN RAT MODEL. Alzheimers & Dementia, 13(7), P232-P233. doi:10.1016/j.jalz.2017.06.072
• Yin, F., Yin, F., Wang, Y., Mishra, A., Mao, J., & Brinton, R. D. (2017). IMPACT OF APOE GENOTYPE ON THE SEX-DIFFERENTIATED BIOENERGETIC TRAJECTORIES AND AD RISKS IN AGING MOUSE BRAINS. Alzheimers & Dementia, 13(7), P664-P664. doi:10.1016/j.jalz.2017.06.797
• Yin, F., Yin, F., Yao, J., Mao, Z., & Brinton, R. D. (2017). FEMALE BRAIN BIOENERGETIC SYSTEM IS REGULATED BY ENDOCRINE AGING: IMPLICATIONS FOR ALZHEIMER'S DISEASE. Alzheimers & Dementia, 13(7), P678-P678. doi:10.1016/j.jalz.2017.06.839
• Zissimopolous, J., Barthold, D., Brinton, R., & Joyce, G. (2017). Sex and Race Differences in the Association of Statin Use and Incidence of Alzheimer’s Disease. JAMA Neurol, 74(2), 225-232. doi:10.1001/jamaneurol.2016.3783
• Brinton, R. (2016). Neuroendocrinology: Oestrogen therapy affects brain structure but not function. Nat Rev Neurol, 12(10), 561-2.
• Harrington, M. G., Yao, J., Trushina, E., Klosinski, L., Harrington, M., Fonteh, A. N., Christensen, T. A., & Brinton, R. D. (2016). PERIMENOPAUSE IN APOE4 BRAIN: ACCELERATED MYELIN CATABOLISM FOR FUEL. Alzheimers & Dementia, 12(7), P656-P657. doi:10.1016/j.jalz.2016.06.1487
• Karim, R., Dang, H., Henderson, H., Hodis, H., St.John, J., Brinton, R., & Mack, W. (2016). Effect of Reproductive History and Exogenous Hormone Use on Cognitive Function in Mid- and Late Life. J Am Geriatr Soc, 64(12), 2448-2456.
• Retberg, J., Dang, H., Hodis, H., Henderson, V., St. John, J., Mack, W., & Brinton, R. (2016). Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: Potential for detecting an at-Alzheimer's risk metabolic phenotype. Neurobiol Aging, 40, 155-63.
• Riedel, B. C., Thompson, P. M., & Brinton, R. D. (2016). Age, APOE and sex: Triad of risk of Alzheimer's disease. The Journal of steroid biochemistry and molecular biology, 160, 134-47.
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  Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer's disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ε4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ε4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ε4 allele. Paradoxically, men homozygous for APOE-ε4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer's disease, age, APOE-ε4 genotype and chromosomal sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the specific risk of the APOE-ε4 positive male which appears to emerge early in the aging process. Evidence for impact of the triad of AD risk factors is most evident in the temporal trajectory of AD progression and burden of pathology in relation to APOE genotype, age and sex. Collectively, the data indicate complex interactions between age, APOE genotype and gender that belies a one size fits all approach and argues for a precision medicine approach that integrates across the three main risk factors for Alzheimer's disease.
• Romani, A., Cervellati, C., Yin, F., Trentini, A., Bennini, T., Fila, E., Bonaccorsi, G., Valacchi, G., & Brinton, R. D. (2016). Brain and serum cholesterol metabolism during perimenopausal transition: A risk factor for Alzheimer's Disease?. Free Radical Biology and Medicine, 96, 41-41. doi:10.1016/j.freeradbiomed.2016.04.084
• Snyder, H., Athana, S., Craft, S., Brinton, R., Dubal, D., Espeland, M., Gatz, M., Mielke, M., & Raber, J. (2016). Sex biology contributions to vulnerability to Alzheimer’s disease: A think tank convened by the Women’s Alzheimer’s Research Initiative. Alzheimer’s & Dementia.
• Solinsky, C. M., Park, J. A., Ichida, J. K., Hennes, V., Chui, H. C., Brinton, R. D., & Blurton-jones, M. (2016). DEVELOPMENT OF IPSC-BASED BIOMARKERS TO IDENTIFY THE PATIENT POPULATION RESPONSIVE TO ALLOPREGNANOLONE. Alzheimers & Dementia, 12(7), P871-P871. doi:10.1016/j.jalz.2016.06.1797
• Solinsky, C. M., Rogawski, M. A., Rodgers, K. E., Irwin, R. W., Brinton, R. D., & Bauer, G. (2016). COMPARATIVE PHARMACOKINETIC ASSESSMENT OF ALLOPREGNANOLONE TO DEVELOP A REGENERATIVE THERAPEUTIC FOR MILD COGNITIVE IMPAIRMENT AND EARLY ALZHEIMER’S DISEASE. Alzheimers & Dementia, 12(7), P430-P430. doi:10.1016/j.jalz.2016.06.820
• Swanson, H. M., Irwin, R. W., & Brinton, R. D. (2016). ALLOPREGNANOLONE PROMOTES CHOLESTEROL AND AMYLOID-BETA CLEARANCE MECHANISMS: ASSESSMENT OF A REGENERATIVE THERAPEUTIC FOR ALZHEIMER’S DISEASE. Alzheimers & Dementia, 12(7), P1024-P1025. doi:10.1016/j.jalz.2016.06.2115
• Wang, Y., & Brinton, R. (2016). Triad of Risk for Late Onset Alzheimer's: Mitochondrial Haplotype, APOE Genotype and Chromosomal Sex. Frontiers in Aging Neuroscience, 8, 232.
• Zhang, L., Trushina, S., Christiansen, T., Bachmeier, B., Gateno, B., Schroeder, A., Yao, J., Itoh, K., Sesaki, H., Poon, W., Gylys, K., Patterson, E., Parisi, J., Brinton, R., Salisbury, J., & Trushina, E. (2016). Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease. Scientific Reports. doi:10.1038/srep18725
• Zhao, L., Mao, Z., Woody, S., & Brinton, R. (2016). Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer's disease.. Neurobiol Aging, 42, 69-79.
• Zissimopolous, J., Barthold, D., Brinton, R., & Joyce, G. (2016). Sex and Race Differences in the Association Between Statin Use and the Incidence of Alzheimer Disease. JAMA Neurol.
• Brinton, R., Yao, J., Yin, F., Mack, W., & Cardenas, E. (2015). Perimenopause as a neurological transition state. Nat Rev Endocrinol.
• Caldwell, C. C., Yao, J., & Brinton, R. D. (2015). Targeting the prodromal stage of Alzheimer's disease: bioenergetic and mitochondrial opportunities. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 12(1), 66-80.
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  Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.
• Esepland, M., Brinton, R., Hugenschmidt, C., Manson, J., Craft, S., Yaffe, K., Weitlauf, J., Vaughan, L., Johnson, K., Padula, C., Jackson, R., & Resnick, S. (2015). Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women.. Diabetes Care.
• Esepland, M., Brinton, R., Manson, J., Yaffe, K., Hugenschmidt, C., Vaughan, L., Craft, S., Edwards, B., Cassanova, R., Masaki, K., & Resnick, S. (2015). Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes. Neurology.
• Geifman, N., Kennedy, R., Buchan, I., & Brinton, R. (2018). Data-driven identification of endophenotypes of Alzheimer’s disease progression: implications for clinical trials and therapeutic interventions. Alzheimer's Research & Therapy.
• Hernandez, G., Franke, L., Chen, Y., Mack, W., Brinton, R., & Schneider, L. (2018). Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor β-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women. Menopause. doi:10.1097/GME.0000000000000984
• Irwin, R., Solinsky, C., Loya, C., Salituro, F., Bauer, G., Rodgers, K. E., Rogawski, M., & Brinton, R. (2015). Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease.. PLoS One, 3(10).
• Karim, R., Koc, M., Rettberg, J., Hodis, H., Henderson, V., St. John, J., Allayee, H., Brinton, R., & Mack, W. (2018). Apolipoprotein E4 Genotype in Combination with Poor Metabolic Profile is Associated with Cognitive Deficit in Healthy Postmenopausal Women: Implications for Late Onset Alzheimer's Disease. PLoS One.
• Karim, R., Stanczyk, F., Brinton, R., Rettberg, J., Hodis, H., & Mack, W. (2015). Association of Edogenous Sex Hormones with Adipokines and Ghrelin in Postmenopausal Women. Clinical Endocrinol Metab, 100(2), 508-15.
• Kosinski, L., Yao, J., Yin, F., Harrington, M., Christiansen, T., Trushina, E., & Brinton, R. (2015). White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease. EBioMedicine.
• Lussier, Y. A., Li, H., Berghout, J., Brinton, R., Vitali, F., & Shang, Y. (2019). Challenges and approaches of systems neurobiology networks to understand the mechanisms and genetic risk of Alzheimer’s Disease. Briefings in Bioinformatics.
• Solinsky, C. M., Rogawski, M. A., Rodgers, K. E., Kim, K., Irwin, R. W., Green, C. E., Brinton, R. D., & Bauer, G. (2015). Allopregnanolone chronic exposure using regenerative treatment regimen: Preclinical ind enabling toxicology indicating safety. Alzheimers & Dementia, 11(7), P472-P473. doi:10.1016/j.jalz.2015.06.518
• Yin, F., Yao, J., Sancheti, H., Feng, T., Melcangi, R. C., Morgan, T. E., Finch, C. E., Pike, C. J., Mack, W. J., Cadenas, E., & Brinton, R. D. (2015). The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity. Neurobiology of aging, 36(7), 2282-95.
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  The perimenopause is an aging transition unique to the female that leads to reproductive senescence which can be characterized by multiple neurological symptoms. To better understand potential underlying mechanisms of neurological symptoms of perimenopause, the present study determined genomic, biochemical, brain metabolic, and electrophysiological transformations that occur during this transition using a rat model recapitulating fundamental characteristics of the human perimenopause. Gene expression analyses indicated two distinct aging programs: chronological and endocrine. A critical period emerged during the endocrine transition from regular to irregular cycling characterized by decline in bioenergetic gene expression, confirmed by deficits in fluorodeoxyglucose-positron emission tomography (FDG-PET) brain metabolism, mitochondrial function, and long-term potentiation. Bioinformatic analysis predicted insulin/insulin-like growth factor 1 and adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK/PGC1α) signaling pathways as upstream regulators. Onset of acyclicity was accompanied by a rise in genes required for fatty acid metabolism, inflammation, and mitochondrial function. Subsequent chronological aging resulted in decline of genes required for mitochondrial function and β-amyloid degradation. Emergence of glucose hypometabolism and impaired synaptic function in brain provide plausible mechanisms of neurological symptoms of perimenopause and may be predictive of later-life vulnerability to hypometabolic conditions such as Alzheimer's.
• Irwin, R. W., & Brinton, R. D. (2014). Allopregnanolone as regenerative therapeutic for Alzheimer's disease: Translational development and clinical promise. PROGRESS IN NEUROBIOLOGY, 113, 40-55.
• Rettberg, J. R., Yao, J., & Brinton, R. D. (2014). Estrogen: A master regulator of bioenergetic. systems in the brain and body. FRONTIERS IN NEUROENDOCRINOLOGY, 35(1), 8-30.
• Rettberg, J. R., Yao, J., & Brinton, R. D. (2014). Estrogen: a master regulator of bioenergetic systems in the brain and body. Frontiers in neuroendocrinology, 35(1), 8-30.
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  Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer's disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral metabolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as indicators of efficacy of hormone therapy or other preventative interventions.
• Sancheti, H., Akopian, G., Yin, F., Brinton, R., & Walsh, J. (2014). Correction: Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer's disease. PLoS ONE, 9(12). doi:10.1371/journal.pone.0116442
• Sancheti, H., Kanamori, K., Patil, I., Brinton, R. D., Ross, B. D., & Cadenas, E. (2014). Reversal of metabolic deficits by lipoic acid in a triple transgenic mouse model of Alzheimer's disease: a C-13 NMR study. JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 34(2), 288-296.
• Solinsky, C. M., Irwin, R. W., & Brinton, R. D. (2014). Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders.. Frontiers in cellular neuroscience, 8, 203. doi:10.3389/fncel.2014.00203
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  Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer's disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer's pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer's mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer's, Parkinson's, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer's disease (AD) that have the potential to accelerate therapeutic translation for multiple unmet neurological needs.
• Yin, F., Zhao, L., Yin, F., Yao, J., Cadenas, E., & Brinton, R. D. (2014). SEX DIFFERENCES IN BIOENERGETIC AGING OF THE BRAIN AND RISK OF ALZHEIMER'S DISEASE. Alzheimers & Dementia, 10(4), P339-P339. doi:10.1016/j.jalz.2014.05.338
• Zhang, W., Sancheti, H., Patil, I., Lin, A., Kanamori, K., Cadenas, E., & Brinton, R. D. (2014). Hypermetabolic state in the 7-month-old triple transgenic mouse model of Alzheimer's disease and the effect of lipoic acid: a 13C-NMR study.. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 34(11), 1749-60. doi:10.1038/jcbfm.2014.137
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  Alzheimer's disease (AD) is characterized by age-dependent biochemical, metabolic, and physiologic changes. These age-dependent changes ultimately converge to impair cognitive functions. This study was carried out to examine the metabolic changes by probing glucose and tricarboxylic acid cycle metabolism in a 7-month-old triple transgenic mouse model of AD (3xTg-AD). The effect of lipoic acid, an insulin-mimetic agent, was also investigated to examine its ability in modulating age-dependent metabolic changes. Seven-month-old 3xTg-AD mice were given intravenous infusion of [1-(13)C]glucose followed by an ex vivo (13)C nuclear magnetic resonance to determine the concentrations of (13)C-labeled isotopomers of glutamate, glutamine, aspartate, gamma aminobutyric acid, and N-acetylaspartate. An intravenous infusion of [1-(13)C]glucose+[1,2-(13)C]acetate was given for different periods of time to distinguish neuronal and astrocytic metabolism. Enrichments of glutamate, glutamine, and aspartate were calculated after quantifying the total ((12)C+(13)C) concentrations by high-performance liquid chromatography. A hypermetabolic state was clearly evident in 7-month-old 3xTg-AD mice in contrast to the hypometabolic state reported earlier in 13-month-old mice. Hypermetabolism was evidenced by prominent increase of (13)C labeling and enrichment in the 3xTg-AD mice. Lipoic acid feeding to the hypermetabolic 3xTg-AD mice brought the metabolic parameters to the levels of nonTg mice.
• Bimonte-nelson, H. A., Brinton, R. D., Singh, M., Simpkins, J. W., Brinton, R. D., & Bimonte-nelson, H. A. (2013). Window of opportunity for estrogen and progestin intervention in brain aging and Alzheimer's disease.. Brain research, 1514, 1-2. doi:10.1016/j.brainres.2013.04.044
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  In 1966, Robert Wilson published the controversial book “Feminine Forever”, in which he listed memory loss as a symptom of menopause (Wilson, 1966). While at the time this claim was not backed with methodical scientific verification, many studies now support the assertion that memory changes occur in women concordant with menopause, relating to accompanying ovarian hormone changes. The U.S. Census Bureau estimates that by 2020, the population of women between 45 and 64 years old will reach approximately 41 million, and will represent 25% of the entire female population in the U.S. This is a marked increase from the 32 million reported for the year 2000 (U.S. Census Bureau. 2004, “U.S. Interim Projections by Age, Sex, Race, and Hispanic Origin,” (http://www.census.gov/ipc/www/usinterim proj/) Internet release date: March 18, 2004). This increasing number of menopausal women will consequently need to make decisions about the use of hormone therapy to treat not only menopausal symptoms, but potentially, to maintain a healthy brain. Recognizing this is critically important, now more than ever, given that women are living approximately one-third of their lives in a menopausal hypo-ovarian hor mone state. Indeed, women are living longer, yet age of spontaneous menopause has remained stable. While research thus far has yielded important insights into rela tions between endogenous and exogenous female steroid effects on the brain and its functions, it is nonetheless true that we have much to learn about the neurobehavioral consequences of the ovarian hormone loss associated with menopause, as well as effects of subsequent hormone ther apy use. Many researchers are working steadfast toward their goal of identifying under what conditions hormone therapies are beneficial, null, or detrimental to cognitive function, as well as mechanisms of these potential impacts. Although numerous basic science studies, epidemiological studies, and some clinical trials have supported the potential benefit of hormone therapy in reducing the incidence of age-associated brain dysfunction, including reducing the risk for Alzheimer's disease, results from the Women's Health Initiative (WHI) have suggested the contrary and left the field unsettled as to the future of hormone therapy. While the latter findings were initially quite unexpected and perhaps even disconcerting to many, the salience of the basic science studies persevered and it is now recognized that many factors that could be interpreted as “caveats” to the WHI (particularly the WHI memory study, WHIMS) are actually critical turning points in the neurobehavioral efficacy of hormone therapy. These putative critical turning points are now being systematically and methodically tested in the preclinical and clinical realm. These include the possibility that both aging and the duration of post-menopausal hormone deprivation diminish the pro tective brain response to steroid hormones (1, 2). This begs the question of whether a finite period of responsivity to estrogens and/or progestins exists; that is, is there a limited window of opportunity around menopause during which hormone therapy can exert positive effects? In order to offer an authoritative perspective on this issue, we invited leaders in the field of steroid hormone neurobiology to offer their insight into five questions: (1) Is there a window of opportu nity for brain protection with hormone therapy in post-menopausal women? (2) Is there evidence for better estrogens and progestins than the estrogen combination conjugated equine estrogens and the progestin medroxypro gesterone acetate, which are the most commonly utilized hormone therapies used to date, and were used in the WHIMS? (3) What are the parameters impacting whether hormone therapy acts as an enhancer or a detriment to the brain and cognition? (4) Are there alternatives to estrogens/ progestins in protecting women from cognitive decline after the menopause? (5) What are the mechanisms underlying the cognitive efficacy of hormone treatment, especially as related to a critical window around menopause? The chapters included in this Special Issue of Brain Research address these five questions through discussion of such topics as the importance of considering the experimental variables, design, and baseline characteristics of the study population in humans, or how the choice of an animal model and tools used to assess such endpoints as cognitive function in rodents can influence outcome and interpretation of the effects of estrogens and progestins, how potential alternatives to estrogens exert their effects on cognitive function and mechanisms related to cognitive function, and the implication of specific receptors and signaling mechanisms in defining the response of the brain to estrogens and/or progesterone. Collectively, we believe that these chapters provide critical information that not only reviews our current understanding of the neurobiology of estrogens and proges-tins, but also offers important insight into the biological basis for the window of opportunity. Identifying the various components of the complex interactions between menopause, hormone therapy, and the brain and its function, including experimental protocols using basic science and clinical evaluations, is the optimal approach to converge the many findings that might currently appear contradictory. In fact, with the continued emergence of new data, including data presented herein, it will likely become clear that the various findings are not contradictory at all. Rather, the variability in effectiveness of hormone therapy is likely dependent on numerous factors that are just starting to be understood, or are not yet taken into account in many studies because they are not yet discovered. As we continue to converge the many perspectives of one scientific problem, such as with the current Special Issue wherein we embody a multidimensional approach to the critical question of a window of opportunity for the neurocognitive effects of hormone therapy, we will align basic science discoveries with clinical findings and interpretations. The hope is that this approach will capitalize on opportunities to make new discoveries, thereby providing subsequent intervention strategies so that women can maximize their potential for healthy brain aging. It is our goal that the window of opportunity for optimal hormone therapy efficacy will expand as new findings emerge and we are able to more explicitly define hormone therapy parameters that enhance brain plasticity, neuroprotection, and cognitive function during aging.
• Brinton, R. (2013). Neurosteroids as regenerative agents in the brain: therapeutic implications. NATURE REVIEWS ENDOCRINOLOGY, 9(4), 241-250.
• Ding, F., Yao, J., Rettberg, J. R., Chen, S., & Brinton, R. D. (2013). Early Decline in Glucose Transport and Metabolism Precedes Shift to Ketogenic System in Female Aging and Alzheimer's Mouse Brain: Implication for Bioenergetic Intervention. PLOS ONE, 8(11).
• Ding, F., Yao, J., Rettberg, J. R., Chen, S., & Brinton, R. D. (2013). Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention. PloS one, 8(11), e79977.
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  We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3-15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6-9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential targets for preventing shifts to less efficient bioenergetic fuels and transition to the ketogenic phenotype of the Alzheimer's brain.
• Ding, F., Yao, J., Zhao, L., Mao, Z., Chen, S., & Brinton, R. D. (2013). Ovariectomy Induces a Shift in Fuel Availability and Metabolism in the Hippocampus of the Female Transgenic Model of Familial Alzheimer's. PLOS ONE, 8(3).
• Ding, F., Yao, J., Zhao, L., Mao, Z., Chen, S., & Brinton, R. D. (2013). Ovariectomy induces a shift in fuel availability and metabolism in the hippocampus of the female transgenic model of familial Alzheimer's. PloS one, 8(3), e59825.
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  Previously, we demonstrated that reproductive senescence in female triple transgenic Alzheimer's (3×TgAD) mice was paralleled by a shift towards a ketogenic profile with a concomitant decline in mitochondrial activity in brain, suggesting a potential association between ovarian hormone loss and alteration in the bioenergetic profile of the brain. In the present study, we investigated the impact of ovariectomy and 17β-estradiol replacement on brain energy substrate availability and metabolism in a mouse model of familial Alzheimer's (3×TgAD). Results of these analyses indicated that ovarian hormones deprivation by ovariectomy (OVX) induced a significant decrease in brain glucose uptake indicated by decline in 2-[(18)F]fluoro-2-deoxy-D-glucose uptake measured by microPET-imaging. Mechanistically, OVX induced a significant decline in blood-brain-barrier specific glucose transporter expression, hexokinase expression and activity. The decline in glucose availability was accompanied by a significant rise in glial LDH5 expression and LDH5/LDH1 ratio indicative of lactate generation and utilization. In parallel, a significant rise in ketone body concentration in serum occurred which was coupled to an increase in neuronal MCT2 expression and 3-oxoacid-CoA transferase (SCOT) required for conversion of ketone bodies to acetyl-CoA. In addition, OVX-induced decline in glucose metabolism was paralleled by a significant increase in Aβ oligomer levels. 17β-estradiol preserved brain glucose-driven metabolic capacity and partially prevented the OVX-induced shift in bioenergetic substrate as evidenced by glucose uptake, glucose transporter expression and gene expression associated with aerobic glycolysis. 17β-estradiol also partially prevented the OVX-induced increase in Aβ oligomer levels. Collectively, these data indicate that ovarian hormone loss in a preclinical model of Alzheimer's was paralleled by a shift towards the metabolic pathway required for metabolism of alternative fuels in brain with a concomitant decline in brain glucose transport and metabolism. These findings also indicate that estrogen plays a critical role in sustaining brain bioenergetic capacity through preservation of glucose metabolism.
• Fuente-Martin, E., Garcia-Caceres, C., Morselli, E., Clegg, D. J., Chowen, J. A., Finan, B., Brinton, R. D., & Tschoep, M. H. (2013). Estrogen, astrocytes and the neuroendocrine control of metabolism. REVIEWS IN ENDOCRINE & METABOLIC DISORDERS, 14(4), 331-338.
• Fuente-Martin, E., Garcia-Caceres, C., Morselli, E., Clegg, D. J., Chowen, J. A., Finan, B., Brinton, R. D., & Tschöp, M. H. (2013). Estrogen, astrocytes and the neuroendocrine control of metabolism. Reviews in endocrine & metabolic disorders, 14(4), 331-8.
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  Obesity, and its associated comorbidities such as type 2 diabetes, cardiovascular diseases, and certain cancers, represent major health challenges. Importantly, there is a sexual dimorphism with respect to the prevalence of obesity and its associated metabolic diseases, implicating a role for gonadal hormones. Specifically, estrogens have been demonstrated to regulate metabolism perhaps by acting as a leptin mimetic in the central nervous system (CNS). CNS estrogen receptors (ERs) include ER alpha (ERα) and ER beta (ERβ), which are found in nuclear, cytoplasmic and membrane sites throughout the brain. Additionally, estrogens can bind to and activate a G protein-coupled estrogen receptor (GPER), which is a membrane-associated ER. ERs are expressed on neurons as well as glia, which are known to play a major role in providing nutrient supply for neurons and have recently received increasing attention for their potentially important involvement in the CNS regulation of systemic metabolism and energy balance. This brief overview summarizes data focusing on the potential role of astrocytic estrogen action as a key component of estrogenic modulation responsible for mediating the sexual dimorphism in body weight regulation and obesity.
• Jiang, T., Cadenas, E., & Brinton, R. D. (2013). PSS257 - Energy - Redox Homeostasis and Inflammation in Brain Aging: Significance of Age-Dependent Astrocyte Metabolic - Redox Profile. Free Radical Biology and Medicine, 65, S115-S116. doi:10.1016/j.freeradbiomed.2013.10.680
• Jiang, T., Yin, F., Yao, J., Brinton, R. D., & Cadenas, E. (2013). Lipoic acid restores age-associated impairment of brain energy metabolism through the modulation of Akt/JNK signaling and PGC1 alpha transcriptional pathway. AGING CELL, 12(6), 1021-1031.
• Sancheti, H., Akopian, G., Yin, F., Brinton, R. D., Walsh, J. P., & Cadenas, E. (2013). Age-Dependent Modulation of Synaptic Plasticity and Insulin Mimetic Effect of Lipoic Acid on a Mouse Model of Alzheimer's Disease. PLOS ONE, 8(7).
• Sancheti, H., Akopian, G., Yin, F., Brinton, R. D., Walsh, J. P., & Cadenas, E. (2013). Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer's disease. PloS one, 8(7), e69830.
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  Alzheimer's disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity have been shown to be affected in the early stages of Alzheimer's disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer's disease (3xTg-AD) that shows progression of pathology as a function of age; two age groups: 6 months (young) and 12 months (old) were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O) and long term potentiation (LTP) (measured by electrophysiology). Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice.
• Schneider, L. S., Rogawski, M. A., Rodgers, K. E., Mack, W. J., Irwin, R. W., Brinton, R. D., & Bauer, G. (2013). Allopregnanolone as a regenerative therapeutic for Alzheimer's disease, 1: From discovery to phase I multiple-ascending-dose clinical trial. Alzheimers & Dementia, 9(4), P709-P709. doi:10.1016/j.jalz.2013.05.1400
• Yao, J., Wong, K., Chen, S., & Brinton, R. D. (2013). Allopregnanolone as a regenerative therapeutic for Alzheimer's disease, 4: Impact on neuronal versus gliosis phenotypic differentiation. Alzheimers & Dementia, 9(4), P710-P710. doi:10.1016/j.jalz.2013.05.1402
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  weeks and then subcutaneously injected with vehicle, Allo (10mg/kg), or 17b-estradiol (E2, 60mg/kg). 24 hours after treatment, mice were sacrificed and brain mitochondria were isolated for mitochondrial respiration and bioenergetic enzyme measurements. Results: Adult NSCs from both nonTg and 3xTgAD mice exhibited a significant age-dependent decline in mitochondrial bioenergetic capacity. Further, aNSC derived from 3xTgAD mice at 6 and 18 months exhibited elevated proton leak. In vitro Allo treatment potentiated mitochondrial respiration in both NSCs, neurons and mixed glia. Further, in vivo Allo treatment restored the OVX-induced decrease in mitochondrial respiration in both nonTg and 3xTgAD mice. Allo treatment increased activity of bioenergetic enzymes such as PDH and aKGDH, and suppressed the OVX-induced increase in lipid peroxidation.Conclusions: There was an ageand Alzheimer’s associated decline in mitochondrial function in aNSCs. Allo treatment potentiated mitochondrial function both in vitro and in vivo. Collectively, these data provided mechanistic basis for developing Allo as a multi-tropic AD therapeutics to sustain and enhance mitochondrial function and to promote neurogenic capacity.
• Yao, J., Wong, K., Irwin, R. W., Chen, S., & Brinton, R. D. (2013). Allopregnanolone as a regenerative therapeutic for Alzheimer's disease, 3: Evidence for potentiation of brain mitochondrial function. Alzheimers & Dementia, 9(4), P709-P710. doi:10.1016/j.jalz.2013.05.1401
• Yao, J., Zhao, L., Mao, Z., Chen, S., Wong, K. C., To, J., & Brinton, R. D. (2013). Potentiation of brain mitochondrial function by S-equol and R/S-equol estrogen receptor β-selective phytoSERM treatments. Brain research, 1514, 128-41.
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  Previously we developed an estrogen receptor β-selective phytoestrogenic (phytoSERM) combination, which contains a mixture of genistein, daidzein, and racemic R/S-equol. The phytoSERM combination was found neuroprotective and non-feminizing both in vitro and in vivo. Further, it prevented or alleviated physical and neurological changes associated with human menopause and Alzheimer's disease. In the current study, we conducted translational analyses to compare the effects of racemic R/S-equol-containing with S-equol-containing phytoSERM therapeutic combinations on mitochondrial markers in rat hippocampal neuronal cultures and in a female mouse ovariectomy (OVX) model. Data revealed that both the S-equol and R/S-equol phytoSERM treatments regulated mitochondrial function, with S-equol phytoSERM combination eliciting greater response in mitochondrial potentiation. Both phytoSERM combination treatments increased expression of key proteins and enzymes involved in energy production, restored the OVX-induced decrease in activity of key bioenergetic enzymes, and reduced OVX-induced increase in lipid peroxidation. Comparative analyses on gene expression profile revealed similar regulation between S-equol phytoSERM and R/S-equol phytoSERM treatments with minimal differences. Both combinations regulated genes involved in essential bioenergetic pathways, including glucose metabolism and energy sensing, lipid metabolism, cholesterol trafficking, redox homeostasis and β-amyloid production and clearance. Further, no uterotrophic response was induced by either of the phytoSERM combinations. These findings indicate translational validity for development of an ER β selective S-equol phytoSERM combination as a nutraceutical to prevent menopause-associated symptoms and to promote brain metabolic activity. This article is part of a Special Issue entitled Hormone Therapy.
• Zhao, L., Mao, Z., Chen, S., Schneider, L. S., & Brinton, R. D. (2013). Early Intervention with an Estrogen Receptor beta-Selective Phytoestrogenic Formulation Prolongs Survival, Improves Spatial Recognition Memory, and Slows Progression of Amyloid Pathology in a Female Mouse Model of Alzheimer's Disease. JOURNAL OF ALZHEIMERS DISEASE, 37(2), 403-419.
• Zhao, L., Schneider, L. S., Mao, Z., & Brinton, R. D. (2013). Estrogen receptor-β regulation of insulin signaling and energy metabolism in APOE- ε2, ε3, ε4 brains. Alzheimers & Dementia, 9(4), P350-P350. doi:10.1016/j.jalz.2013.05.657
• Zhao, L., Stanczyk, F. Z., Schneider, L. S., Rettberg, J. R., Mack, W. J., Hodis, H. N., Dang, H., & Brinton, R. D. (2013). A bioenergetic trajectory of female brain aging and Alzheimer's disease 3: Development of metabolic and physiological biomarker profiles for early detection of women at risk for Alzheimer's disease. Alzheimers & Dementia, 9(4), P348-P349. doi:10.1016/j.jalz.2013.05.652
• Zhao, L., Yao, J., Mao, Z., Klosinski, L., Chen, S., & Brinton, R. D. (2013). P2-008: A bioenergetic trajectory of female brain aging and Alzheimer's disease 2: Mechanistic link between mitochondrial dysfunction and white matter degeneration in the normal mammalian aging female brain. Alzheimers & Dementia, 9(4), P348-P348. doi:10.1016/j.jalz.2013.05.650
• Zhao, L., Yao, J., Rettberg, J. R., Klosinski, L., Ding, F., Chen, S., & Brinton, R. D. (2013). P2-011: A bioenergetic trajectory of female brain aging and Alzheimer's disease 1: Implications for risk prevention and treatment. Alzheimers & Dementia, 9(4), P349-P349. doi:10.1016/j.jalz.2013.05.653
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  Background: The prodromal phase of Alzheimer’s disease begins decades prior to clinically detectable dementia; thus, identification of early biomarkers is critical to identifying at-risk populations. Metabolic changes in the brain are among the earliest features of the Alzheimer’s pathological cascade. Estrogen positively regulates the bioenergetic system of the brain from glucose uptake to ATP generation. Additionally, estrogen regulates peripheral adipose tissue distribution and promotes healthy fasting insulin and glucose levels. Consequently, loss of ovarian hormones at menopause could lead to a state of bioenergetic and metabolic crisis that puts women at increased risk for AD. Methods:Clinical data and plasma samples were obtained from women enrolled in the Early vs. Late Intervention Trial with Estradiol (ELITE). Nine metabolic biomarkers were assessed. Metabolic biomarker clusters were determined using principal components analysis followed by k-means clustering. Metabolic clusters were stratified by early or late-menopause, and correlated with cognitive performance. Results: Preliminary results of metabolic variables measured at 6 months generated three distinct clusters. Women in Cluster 1 had a healthy metabolic profile; women in Cluster 2 had a metabolic profile indicating risk of diabetes; and women in Cluster 3 had a pre-hypertensive metabolic profile. Compared to women in Cluster 1, women in Cluster 2 showed significantly worse baseline scores on the Trail-Making Test, Part B (p < 0.05). Preliminary data are consistent with a profile for risk of metabolic and cognitive decline with the menopausal transition. Further analyses are in progress; baseline and longitudinal cluster data will be presented at the conference. Conclusions: Outcomes of these analyses will provide metabolic profiles of women at risk for cognitive decline with age and menopause.
• Zhu, M., Yao, J., To, J., Rodgers, K. E., Irwin, R. W., Chen, S., Brinton, R. D., & Bolger, M. B. (2013). Allopregnanolone as a regenerative therapeutic for Alzheimer's disease, 2: Bridging subcutaneous to intravenous formulations for clinical trials. Alzheimers & Dementia, 9(4), P710-P711. doi:10.1016/j.jalz.2013.05.1404
• Adeosun, S. O., Hou, X. u., Jiao, Y., Zheng, B., Henry, S., Hill, R., He, Z., Pani, A., Kyle, P., Ou, X., Mosley, T., Farley, J. M., Stockmeier, C., Paul, I., Bigler, S., Brinton, R. D., Smeyne, R., & Wang, J. M. (2012). Allopregnanolone Reinstates Tyrosine Hydroxylase Immunoreactive Neurons and Motor Performance in an MPTP-Lesioned Mouse Model of Parkinson's Disease. PLOS ONE, 7(11).
• Bali, N., Arimoto, J. M., Iwata, N., Lin, S. W., Zhao, L., Brinton, R. D., Morgan, T. E., & Finch, C. E. (2012). Differential Responses of Progesterone Receptor Membrane Component-1 (Pgrmc1) and the Classical Progesterone Receptor (Pgr) to 17 beta-Estradiol and Progesterone in Hippocampal Subregions that Support Synaptic Remodeling and Neurogenesis. ENDOCRINOLOGY, 153(2), 759-769.
• Irwin, R. W., Yao, J., To, J., Hamilton, R. T., Cadenas, E., & Brinton, R. D. (2012). Selective Oestrogen Receptor Modulators Differentially Potentiate Brain Mitochondrial Function. JOURNAL OF NEUROENDOCRINOLOGY, 24(1), 236-248.
• Jayaraman, A., Carroll, J. C., Morgan, T. E., Lin, S., Zhao, L., Arimoto, J. M., Murphy, M. P., Beckett, T. L., Finch, C. E., Brinton, R. D., & Pike, C. J. (2012). 17 beta-Estradiol and Progesterone Regulate Expression of beta-Amyloid Clearance Factors in Primary Neuron Cultures and Female Rat Brain. ENDOCRINOLOGY, 153(11), 5467-5479.
• Jayaraman, A., Carroll, J. C., Morgan, T. E., Lin, S., Zhao, L., Arimoto, J. M., Murphy, M. P., Beckett, T. L., Finch, C. E., Brinton, R. D., & Pike, C. J. (2012). 17β-estradiol and progesterone regulate expression of β-amyloid clearance factors in primary neuron cultures and female rat brain. Endocrinology, 153(11), 5467-79.
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  The accumulation of β-amyloid protein (Aβ) is a key risk factor in the development of Alzheimer's disease. The ovarian sex steroid hormones 17β-estradiol (E(2)) and progesterone (P(4)) have been shown to regulate Aβ accumulation, although the underlying mechanism(s) remain to be fully elucidated. In this study, we investigate the effects of E(2) and P(4) treatment on the expression levels of Aβ clearance factors including insulin-degrading enzyme, neprilysin, endothelin-converting enzyme 1 and 2, angiotensin-converting enzyme, and transthyretin, both in primary neuron cultures and female rat brains. Our results show that E(2) and P(4) affect the expression levels of several Aβ clearance factors in dose- and time-dependent manners. Most notably, expression of insulin-degrading enzyme is significantly increased by both hormones in cultured neurons and in vivo and is inversely associated with the soluble Aβ levels in vivo. These findings further define sex steroid hormone actions involved in regulation of Aβ, a relationship potentially important to therapeutic approaches aimed at reducing risk of Alzheimer's disease.
• Reiman, E. M., Brinton, R. D., Katz, R., Petersen, R. C., Negash, S., Mungas, D., & Aisen, P. S. (2012). Considerations in the design of clinical trials for cognitive aging. The journals of gerontology. Series A, Biological sciences and medical sciences, 67(7), 766-72.
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  What will it take to develop interventions for the treatment of age-related cognitive decline? Session V of the Summit provided perspectives on the design of clinical trials to evaluate promising but unproven interventions, and some of the steps needed to accelerate the discovery and evaluation of promising treatments. It considered strategies to further characterize the biological and cognitive changes associated with normal aging and their translation into the development of new treatments. It provided regulatory, scientific, and clinical perspectives about neurocognitive aging treatments, their potential benefits and risks, and the strategies and endpoints needed to evaluate them in the most rapid, rigorous, and clinically meaningful way. It considered lessons learned from the study of Alzheimer's disease, the promising roles of biomarkers in neurocognitive aging research, and ways to help galvanize the scientific study and treatment of neurocognitive aging.
• Singh, C., Liu, L., Wang, J. M., Irwin, R. W., Yao, J., Chen, S., Henry, S., Thompson, R. F., & Brinton, R. D. (2012). Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice. NEUROBIOLOGY OF AGING, 33(8), 1493-1506.
• Singh, C., Liu, L., Wang, J. M., Irwin, R. W., Yao, J., Chen, S., Henry, S., Thompson, R. F., & Brinton, R. D. (2012). Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice. Neurobiology of aging, 33(8), 1493-506.
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  We previously demonstrated that allopregnanolone (APα) increased proliferation of neural progenitor cells and reversed neurogenic and cognitive deficits prior to Alzheimer's disease (AD) pathology (Wang, J.M., Johnston, P.B., Ball, B.G., Brinton, R.D., 2005. The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J. Neurosci. 25, 4706-4718; Wang, J.M., Singh, C., Liu, L., Irwin, R.W., Chen, S., Chung, E.J., Thompson, R.F., Brinton, R.D., 2010. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 107, 6498-6503). Herein, we determined efficacy of APα to restore neural progenitor cell survival and associative learning and memory subsequent to AD pathology in male 3xTgAD mice and their nontransgenic (nonTg) counterparts. APα significantly increased survival of bromodeoxyuridine positive (BrdU+) cells and hippocampal-dependent associative learning and memory in 3xTgAD mice in the presence of intraneuronal amyloid beta (Aβ) whereas APα was ineffective subsequent to development of extraneuronal Aβ plaques. Restoration of hippocampal-dependent associative learning was maximal by the first day and sustained throughout behavioral training. Learning and memory function in APα-treated 3xTgAD mice was 100% greater than vehicle-treated and comparable to maximal normal nonTg performance. In aged 15-month-old nonTg mice, APα significantly increased survival of bromodeoxyuridine-positive cells and hippocampal-dependent associative learning and memory. Results provide preclinical evidence that APα promoted survival of newly generated cells and restored cognitive performance in the preplaque phase of AD pathology and in late-stage normal aging.
• Sun, C., Ou, X., Farley, J. M., Stockmeier, C., Bigler, S., Brinton, R. D., & Wang, J. M. (2012). Allopregnanolone Increases the Number of Dopaminergic Neurons in Substantia Nigra of a Triple Transgenic Mouse Model of Alzheimer's Disease. CURRENT ALZHEIMER RESEARCH, 9(4), 473-480.
• Sun, C., Ou, X., Farley, J. M., Stockmeier, C., Bigler, S., Brinton, R. D., & Wang, J. M. (2012). Allopregnanolone increases the number of dopaminergic neurons in substantia nigra of a triple transgenic mouse model of Alzheimer's disease. Current Alzheimer research, 9(4), 473-80.
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  More than a third of Alzheimer's disease (AD) patients show nigrostriatal pathway disturbances, resulting in akinesia (inability to initiate movement) and bradykinesia (slowness of movement). The high prevalence of this dysfunction of dopaminergic neuron in the nigrostriatal pathway in AD suggests that the risk factors for AD appear also significant risk factors for substantia nigra pars compacta (SNpc) lesions. Previously, we have demonstrated that allopregnanolone (APα) promotes neurogenesis and improves the cognitive function in a triple transgenic mouse model of AD (3xTgAD). In this study, we sought to exam 1) the SNpc lesions in 3xTgAD mice and 2) the impact of APα on promoting the regeneration of new dopaminergic neurons in SNpc of the 3xTgAD mice. The number of Nissl-stained total neurons, tyrosine hydroxylase (TH) positive neurons, and BrdU/TH double positive newly formed neurons were analyzed with unbiased stereology. In the SNpc of 3xTgAD mice, TH positive neurons was 47+- 18 % (p = 0.007), total neurons was 62 +-11.6 % (p = 0.016), of those in the SNpc of non-Tg mice, respectively. APα treatment increased the TH positive neurons in the SNpc of 3xTgAD mice to 93.2 +- 18.5 (p = 0.021 vs. 3xTgAD vehicle) and the total neurons to 84.9+- 6.6 (p = 0.046 vs. 3xTgAD vehicle) of non-Tg mice. These findings indicate that there is a loss of neurons, specifically the TH positive neurons in SNpc of 3xTgAD mice, and that APα reverses the lesion in SNpc of 3xTgAD by increasing the formation of new TH neurons.
• Tusty, M., Johnstone, T. B., Hogenkamp, D. J., Gee, K. W., Chen, S., & Brinton, R. D. (2012). Allopregnanolone analogues promote proliferation of neural progenitor cells. Alzheimers & Dementia, 8(4), P401-P401. doi:10.1016/j.jalz.2012.05.1105
• Wang, J. M., Hou, X. u., Adeosun, S., Hill, R., Henry, S., Paul, I., Irwin, R. W., Ou, X., Bigler, S., Stockmeier, C., Brinton, R. D., & Gomez-Sanchez, E. (2012). A Dominant Negative ER beta Splice Variant Determines the Effectiveness of Early or Late Estrogen Therapy after Ovariectomy in Rats. PLOS ONE, 7(3).
• Yao, J., & Brinton, R. D. (2012). Estrogen regulation of mitochondrial bioenergetics: implications for prevention of Alzheimer's disease. Advances in pharmacology (San Diego, Calif.), 64, 327-71.
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  Alzheimer's disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid. Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance. Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The "healthy cell bias of estrogen action" hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy.
• Yao, J., Irwin, R., Chen, S., Hamilton, R., Cadenas, E., & Brinton, R. D. (2012). Ovarian hormone loss induces bioenergetic deficits and mitochondrial beta-amyloid. NEUROBIOLOGY OF AGING, 33(8), 1507-1521.
• Yao, J., Irwin, R., Chen, S., Hamilton, R., Cadenas, E., & Brinton, R. D. (2012). Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid. Neurobiology of aging, 33(8), 1507-21.
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  Previously, we demonstrated that reproductive senescence was associated with mitochondrial deficits comparable to those of female triple-transgenic Alzheimer's mice (3xTgAD). Herein, we investigated the impact of chronic ovarian hormone deprivation and 17β-estradiol (E2) replacement on mitochondrial function in nontransgenic (nonTg) and 3xTgAD female mouse brain. Depletion of ovarian hormones by ovariectomy (OVX) in nontransgenic mice significantly decreased brain bioenergetics, and induced mitochondrial dysfunction and oxidative stress. In 3xTgAD mice, OVX significantly exacerbated mitochondrial dysfunction and induced mitochondrial β-amyloid and β-amyloid (Aβ)-binding-alcohol-dehydrogenase (ABAD) expression. Treatment with E2 at OVX prevented OVX-induced mitochondrial deficits, sustained mitochondrial bioenergetic function, decreased oxidative stress, and prevented mitochondrial β-amyloid and ABAD accumulation. In vitro, E2 increased maximal mitochondrial respiration in neurons and basal and maximal respiration in glia. Collectively, these data demonstrate that ovarian hormone loss induced a mitochondrial phenotype comparable to a transgenic female model of Alzheimer's disease (AD), which was prevented by E2. These findings provide a plausible mechanism for increased risk of Alzheimer's disease in premenopausally oophorectomized women while also suggesting a therapeutic strategy for prevention.
• Yao, J., Mao, Z., Ding, F., Chen, S., Cadenas, E., & Brinton, R. D. (2012). Shift in brain mitochondrial bioenergetics in aging and Alzheimer's: Implications for disease prevention and treatment. Alzheimers & Dementia, 8(4), P714-P714. doi:10.1016/j.jalz.2012.05.1931
• Yao, J., Reiman, E. M., Mao, Z., Luo, J., Ding, F., Chen, S., Chen, K., & Brinton, R. D. (2012). Ovarian hormone loss induced decline in glucose availability and shift to alternative substrates in brain. Alzheimers & Dementia, 8(4), P153-P153. doi:10.1016/j.jalz.2012.05.412
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  Background: Reproductive senescence is associated with decline in brain mitochondrial function. Further, enzymes for ketogenic/fatty acid metabolism were significantly increased, indicating shift towards a ketogenic phenotype. Herein, we investigated impact of reproductive senescence and ovarian hormone loss on brain substrate system. Methods: Aging female mice underwent FDG-MicroPET/Micro-CT imagin g, followed by analyses of brain bioenergetic substrates and their transporter profile. 6-month Female mice were also ovariectomized and underwent FDG-MicroPET/Micro-CT imagin g. Initial analysis was conducted to assess whole brain glucose uptake. ROI analyses were conducted in collaboration with Drs. Chen and Reiman and colleagues.Results:Age-related decline in brain glucose uptake was statistically significant at 9-month-of-age in the female mouse brain. Pathway analyses identified a concomitant decline in hexokinase activity, neuronal glucose transporter (GLUT3) expression and increased neuronal monocarboxylate transporter expression (MCT2), indicating a decline in glucose metabolism and increased transport of alternative fuels, ketone bodies or/and lactate in brains. However, MCT1 in BBB and astrocytes significantly decreased at 12-month-of-age, indicative of decreased transport of alternative substrates. Because these changes occurred during the period of reproductive senescence, we investigated regulation of substrate transport system by ovarian hormones. Contrary to expectation, the GLUTs increased in the absence of ovarian hormones. However, the increase in glucose transporters did not result in an increase in brain glucose uptake as brain glucose uptake was significantly decreased in OVX-female brain. These data indicate that despite the increase in GLUTs, the function of these transporters was compromised. Regional analyses indicated that glucose metabolism was significantly decreased in thalamus, consistent with hypometabolism in ApoE4-carriers. Estrogen treatment at the time of OVX prevented decline in transporters and brain glucose uptake to sustain brain metabolism.Conclusions:Reproductive senescence is associated with a decline in transporters for both glucose and ketone bodies, adaptive responses to increase substrate transporters is thwarted by post-translational modifications. Within 5 weeks of ovarian hormone loss, which translates into 2-3 years of human life span, thalamic hypometabolism developed, which is evident in ApoE4 Latino carriers, at-risk for AD. Estrogen treatment at the time of ovariectomy prevented declines in transporter expression and function, evidenced by brain glucose uptake.
• Zhao, L., Mao, Z., & Brinton, R. D. (2012). Activation of estrogen receptor beta promotes IRS/PI3K/AKT/GSK3B-mediated insulin signaling in the female brain: Implications for anti-aging and Alzheimer's prevention. Alzheimers & Dementia, 8(4), P645-P645. doi:10.1016/j.jalz.2012.05.1727
• Zhao, L., Morgan, T. E., Mao, Z., Lin, S., Cadenas, E., Finch, C. E., Pike, C. J., Mack, W. J., & Brinton, R. D. (2012). Continuous versus Cyclic Progesterone Exposure Differentially Regulates Hippocampal Gene Expression and Functional Profiles. PLOS ONE, 7(2).
• Zhao, L., Stanczyk, F. Z., Rettberg, J. R., Mack, W. J., Hodis, H. N., & Brinton, R. D. (2012). Biomarkers of metabolic function for early detection of women at risk for Alzheimer's disease. Alzheimers & Dementia, 8(4), P281-P282. doi:10.1016/j.jalz.2012.05.757
• Zhao, L., Yao, J., Mao, Z., Ding, F., Cadenas, E., & Brinton, R. D. (2012). Effects of age and reproductive status on gene expression in the female hippocampus. Alzheimers & Dementia, 8(4), P305-P305. doi:10.1016/j.jalz.2012.05.834
• Zheng, B., Wang, J. M., Paul, I. A., Irwin, R. W., Hou, X., Brinton, R. D., & Adeosun, S. O. (2012). Motor deficits in mouse models of Alzheimer's disease. Alzheimers & Dementia, 8(4), P670-P671. doi:10.1016/j.jalz.2012.05.1813
• Zhu, M., Irwin, R. W., Chen, S., & Brinton, R. D. (2012). Allopregnanolone as a regenerative drug candidate in a female mouse model of Alzheimer's disease. Alzheimers & Dementia, 8(4), P398-P398. doi:10.1016/j.jalz.2012.05.1096
• Zhu, M., Wang, J. M., Rodgers, K. E., Irwin, R. W., Hernandez, E., Chen, S., Brinton, R. D., & Bolger, M. B. (2012). Allopregnanolone as a regenerative therapeutic for Alzheimer's: Formulation development for clinical trials. Alzheimers & Dementia, 8(4), P400-P400. doi:10.1016/j.jalz.2012.05.1103
• Chen, S., Wang, J. M., Irwin, R. W., Yao, J., Liu, L., & Brinton, R. D. (2011). Allopregnanolone Promotes Regeneration and Reduces beta-Amyloid Burden in a Preclinical Model of Alzheimer's Disease. PLOS ONE, 6(8).
• Hamilton, R. T., Rettberg, J. R., Mao, Z., To, J., Zhao, L., Appt, S. E., Register, T. C., Kaplan, J. R., & Brinton, R. D. (2011). Hippocampal responsiveness to 17 beta-estradiol and equol after long-term ovariectomy: Implication for a therapeutic window of opportunity. BRAIN RESEARCH, 1379, 11-22.
• Irwin, R. W., Yao, J., Ahmed, S. S., Hamilton, R. T., Cadenas, E., & Brinton, R. D. (2011). Medroxyprogesterone Acetate Antagonizes Estrogen Up-Regulation of Brain Mitochondrial Function. ENDOCRINOLOGY, 152(2), 556-567.
• Rettberg, J. R., Hamilton, R. T., Mao, Z., To, J., Zhao, L., Appt, S. E., Register, T. C., Kaplan, J. R., & Brinton, R. D. (2011). The effect of dietary soy isoflavones before and after ovariectomy on hippocampal protein markers of mitochondrial bioenergetics and antioxidant activity in female monkeys. Brain research, 1379, 23-33.
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  Estrogen therapy can promote cognitive function if initiated within a 'critical window' during the menopausal transition. However, in the absence of a progestogen, estrogens increase endometrial cancer risk which has spurred research into developing estrogenic alternatives that have the beneficial effects of estrogen but which are clinically safer. Soy protein is rich in isoflavones, which are a class of potential estrogenic alternatives. We sought to determine the effects of two diets, one with casein-lactalbumin as the main protein source and the other with soy protein containing isoflavones, on protein markers of hippocampal bioenergetic capacity in adult female cynomolgus macaques (Macaca fascicularis). Further, we assessed the effects of dietary soy isoflavones before or after ovariectomy. Animals receiving soy diet premenopausally then casein/lactalbumin post-ovariectomy had higher relative hippocampal content of glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase and pyruvate dehydrogenase subunit e1α. Post-ovariectomy consumption of soy was associated with higher succinate dehydrogenase α levels and lower levels of isocitrate dehydrogenase, both proteins involved in the tricarboxylic acid cycle, significantly decreased expression of the antioxidant enzyme peroxiredoxin-V, and a non-significant trend towards decreased manganese superoxide dismutase expression. None of the diet paradigms significantly affected expression levels of oxidative phosphorylation enzyme complexes, or of mitochondrial fission and fusion proteins. Together, these data suggest that long-term soy diet produces minimal effects on hippocampal expression of proteins involved in bioenergetics, but that switching between a diet containing primarily animal protein and one containing soy isoflavones before and after menopause may result in complex effects on brain chemistry.
• Wang, J. M., Irwin, R. W., Chen, S., & Brinton, R. D. (2011). Neuroregenerative mechanisms of allopregnanolone in Alzheimer's disease.. Frontiers in endocrinology, 2, 117. doi:10.3389/fendo.2011.00117
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  The proliferative pool and regenerative potential of neural stem cells diminishes with age, a phenomenon that may be exacerbated in prodromal and mild Alzheimer's disease (AD) brains. In parallel, the neuroactive progesterone metabolite, allopregnanolone (APα), along with a host of other factors, is decreased in the AD brain. Results of preclinical analyses demonstrate that APα is a potent inducer of neural progenitor proliferation of both rodent and human derived neural progenitor cells in vitro. In vivo, APα significantly increased neurogenesis within the subgranular zone of the dentate gyrus and subventricular zone of the 3xTgAD mouse model. Functionally, APα reversed the learning and memory deficits of 3xTgAD mice prior to and following the onset of AD pathology and was comparably efficacious in aged normal mice. In addition to inducing regenerative responses in mouse models of AD, APα significantly reduced beta-amyloid burden, beta-amyloid binding alcohol dehydrogenase load, and microglial activation. In parallel, APα increased markers of white matter generation and cholesterol homeostasis. Analyses to determine the optimal treatment regimen in the 3xTgAD mouse brain indicated that a treatment regimen of APα once per week was optimal for both inducing neurogenesis and reducing AD pathology. Pharmacokinetic analyses indicated that APα is rapidly increased in both plasma and brain following a single dose. APα is most efficacious when administered once per week which will contribute to its margin of safety. Further, analyses in both animals and humans have provided parameters for safe APα dosage exposure in humans. From a translational perspective, APα is a small molecular weight, blood brain barrier penetrant molecule with substantial preclinical efficacy data as a potential Alzheimer's therapeutic with existing safety data in animals and humans. To our knowledge, APα is the only small molecule that both promotes neural progenitor regeneration in brain and simultaneously reduces AD pathology burden.
• Wang, J. M., Singh, C., She, H., Foy, M. R., Chen, S., Brinton, R. D., & Bortolato, M. (2011). Preclinical development of allopregnanolone to restore cognitive function in a mouse model of Alzheimer's disease: transdermal and intranasal drug delivery. Alzheimers & Dementia, 7(4), S477-S478. doi:10.1016/j.jalz.2011.05.1388
• Wong, W. W., Weaver, C. M., Utian, W. H., Shu, X. O., Setchell, K. D., Setchell, D. R., Messina, M., Maki, P. M., Landgren, B. M., Kronenberg, F., Kim, H., Ishimi, Y., Hodis, H. N., Gold, E. B., Gallagher, J. C., Frankenfeld, C. L., Cline, J. M., Clarkson, T. B., Brinton, R. D., , Basaria, S. S., et al. (2011). The role of soy isoflavones in menopausal health: report of The North American Menopause Society/Wulf H. Utian Translational Science Symposium in Chicago, IL (October 2010).. Menopause (New York, N.Y.), 18(7), 732-53. doi:10.1097/gme.0b013e31821fc8e0
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  If and to what extent soy protein, soy isoflavones, and their metabolites, including S(--)-equol, have beneficial effects on women's health is currently unclear. The North American Menopause Society (NAMS)/Utian Translational Science Symposium on Soy and Soy Isoflavones convened October 9-10, 2010, to clarify basic and clinical research findings as they relate to the risk and benefits of soy products for peri- and postmenopausal women..A working group of faculty and panelists composed of clinical and research experts in the fields of women's health and botanicals met during a 2-day translational symposium to cover the latest evidence-based science on isoflavones as they affect menopausal symptoms, breast and endometrial cancer, atherosclerosis, bone loss, and cognition. Full descriptions of the bioavailability and pharmacokinetics of isoflavones were also presented. Subspecialty groups then broke off with the goal of translating the information into a report for general medical practice and identifying further research areas. All faculty and panelists reviewed the final report, which was then approved by the NAMS Board of Trustees..From the hundreds of studies reviewed in this report, there are mixed results of the effects on midlife women. Soy-based isoflavones are modestly effective in relieving menopausal symptoms; supplements providing higher proportions of genistein or increased in S(--)-equol may provide more benefits. Soy food consumption is associated with lower risk of breast and endometrial cancer in observational studies. The efficacy of isoflavones on bone has not been proven, and the clinical picture of whether soy has cardiovascular benefits is still evolving. Preliminary findings on cognitive benefit from isoflavone therapy support a "critical window" hypothesis wherein younger postmenopausal women derive more than older women..Several areas for further research have been identified on soy and midlife women. More clinical studies are needed that compare outcomes among women whose intestinal bacteria have the ability to convert daidzein to equol (equol producers) with those that lack that ability (equol nonproducers) in order to determine if equol producers derive greater benefits from soy supplementation. Larger studies are needed in younger postmenopausal women, and more research is needed to understand the modes of use of soy isoflavone supplements in women. The interrelations of other dietary components on soy isoflavones consumed as a part of diet or by supplement on equol production also require further study, as do potential interactions with prescription and over-the-counter medications. And finally, greater standardization and documentation of clinical trial data of soy are needed.
• Wu, T., Chen, S., & Brinton, R. D. (2011). Membrane estrogen receptors mediate calcium signaling and MAP kinase activation in individual hippocampal neurons. BRAIN RESEARCH, 1379, 34-43.
• Yao, J., & Brinton, R. D. (2011). Targeting mitochondrial bioenergetics for Alzheimer's prevention and treatment. Current pharmaceutical design, 17(31), 3474-9.
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  Alzheimer's is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. The progressive and multifaceted degenerative phenotype of Alzheimer's suggests that successful treatment strategies necessarily will be equally multi-faceted and disease stage specific. Traditional therapeutic strategies based on the pathological aspect of the disease have achieved success in preclinical models which has not translated into clinical therapeutic efficacy. Meanwhile, increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. The essential role of mitochondrial bioenergetics and the unique trajectory of alterations in brain metabolic capacity enable a bioenergetic- centric strategy that targets disease-stage specific pattern of brain metabolism for disease prevention and treatment. A combination of nutraceutical and pharmaceutical intervention that enhances glucose-driven metabolic activity and potentiates mitochondrial bioenergetic function could prevent the antecedent decline in brain glucose metabolism, promote healthy aging and prevent AD. Alternatively, during the prodromal incipient phase of AD, sustained activation of ketogenic metabolic pathways coupled with supplement of the alternative fuel source, ketone bodies, could sustain mitochondrial bioenergetic function to prevent or delay further progression of the disease.
• Yao, J., Cadenas, E., & Brinton, R. D. (2011). Estrogen, Mitochondrial Bioenergetics and Alzheimer's Disease.. Biology of Reproduction, 85(Suppl_1), 99-99. doi:10.1093/biolreprod/85.s1.99
• Yao, J., Chen, S., Cadenas, E., & Brinton, R. D. (2011). Estrogen protection against mitochondrial toxin-induced cell death in hippocampal neurons: Antagonism by progesterone. BRAIN RESEARCH, 1379, 2-10.
• Yao, J., Chen, S., Mao, Z., Cadenas, E., & Brinton, R. D. (2011). 2-Deoxy-D-Glucose Treatment Induces Ketogenesis, Sustains Mitochondrial Function, and Reduces Pathology in Female Mouse Model of Alzheimer's Disease. PLOS ONE, 6(7).
• Yao, J., Mao, Z., Irwin, R. W., Chen, S., Cadenas, E., & Brinton, R. D. (2011). Preclinical efficacy of 2-Deoxyglucose to sustain mitochondrial metabolic function and delay progression of Alzheimer's pathology. Alzheimers & Dementia, 7(4), S667-S668. doi:10.1016/j.jalz.2011.05.1921
• Yao, J., Rettberg, J. R., Klosinski, L. P., Cadenas, E., & Brinton, R. D. (2011). Shift in brain metabolism in late onset Alzheimer's disease: Implications for biomarkers and therapeutic interventions. MOLECULAR ASPECTS OF MEDICINE, 32(4-6), 247-257.
• Yao, J., Rettberg, J. R., Klosinski, L. P., Cadenas, E., & Brinton, R. D. (2011). Shift in brain metabolism in late onset Alzheimer's disease: implications for biomarkers and therapeutic interventions. Molecular aspects of medicine, 32(4-6), 247-57.
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  Alzheimer's is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised mitochondrial bioenergetics lead to over-production of and mitochondrial accumulation of β-amyloid, which is coupled with oxidative stress. Collectively, this results in a shift in brain metabolic profile from glucose-driven bioenergetics towards a compensatory, but less efficient, ketogenic pathway. We propose that the compensatory shift from a primarily aerobic glycolysis pathway to a ketogenic/fatty acid β-oxidation pathway eventually leads to white matter degeneration. The essential role of mitochondrial bioenergetics and the unique trajectory of compensatory metabolic adaptations in brain enable a bioenergetic-centric strategy for development of biomarkers. From a therapeutic perspective, this trajectory of alterations in brain metabolic capacity enables disease-stage specific strategies to target brain metabolism for disease prevention and treatment. A combination of nutraceutical and pharmaceutical interventions that enhance glucose-driven metabolic activity and potentiate mitochondrial bioenergetic function could prevent the antecedent decline in brain glucose metabolism, promote healthy aging and prevent AD. Alternatively, during the prodromal incipient phase of AD, sustained activation of ketogenic metabolic pathways coupled with supplementation of the alternative fuel source, ketone bodies, could sustain mitochondrial bioenergetic function to prevent or delay further progression of the disease.
• Zhao, L., Schneider, L. S., Mao, Z., & Brinton, R. D. (2011). Estrogen receptor β-selective phytoestrogenic formulation prevents physical and neurological changes in a preclinical model of human menopause.. Menopause (New York, N.Y.), 18(10), 1131-42. doi:10.1097/gme.0b013e3182175b66
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  As an alternative to estrogen therapy, the efficacy of an estrogen receptor β-selective phytoestrogenic (phyto-β-SERM) formulation to regulate climacteric symptoms and decline in brain responses associated with ovarian hormone loss in menopause was assessed..A phyto-β-SERM formulation-containing diet was compared with a commercial soy extract diet and a phytoestrogen-free base/control diet in an ovariectomized (OVX) mouse model of human menopause. Two treatment studies were conducted: (1) a 2-month study assessed the effects of experimental diets on tail skin temperature as a model of menopausal hot flashes, and (2) a 9-month study assessed the long-term impact of the diets on overall health, hair thinning/loss, spatial working memory, and associated protein expression in the hippocampus..The phyto-β-SERM diet prevented OVX-induced menopause-like changes including the rise in skin temperature, hair thinning/loss, deficit in spatial memory function, and reversed OVX-induced decline in the expression of hippocampal proteins involved in neural plasticity and β-amyloid degradation/clearance. The soy extract diet had no effect or exacerbated OVX-induced changes..Overall, the phyto-β-SERM diet induced physical and neurological responses comparable with ovary-intact mice, suggesting the therapeutic potential of the phyto-β-SERM formulation for the prevention/alleviation of climacteric symptoms and decline in brain responses induced by ovarian hormone loss, which provides the basis for further work in postmenopausal women.
• Zhao, L., Schneider, L. S., Mao, Z., & Brinton, R. D. (2011). Phyto-beta-SERM formulation for menopause and Alzheimer's disease: From bench to bedside. Alzheimers & Dementia, 7(4), S669-S669. doi:10.1016/j.jalz.2011.05.1925
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  a traditional Chinese medicinal herb, has been used for thousands of years as a tonic and anti-aging agent, and frequently used to treat dementia in China. 2,3,5,4’-tetrahydroxy stilbene-2-O-s-D-glucoside (TSG) is one of the active components extracted from Polygonum multiflorum, showing obviously neuroprotection effects in several AD-like models, but the exact mechanism is still not understood. To investigate the pharmacological mechanisms of TSG on AD therapy, we observed the lesion of MAPKs signal transduction pathway in the brain of different age AD-like transgenic animal and cellular models and to explore the protective effect of the drug. Methods: APP695V717I transgenic (Tg) mice were observed from 4 to 16 month old. The Tg mice were randomly divided into model group (4 month, 10 month and 16 month old), and TSG group at dose of 0.05,0.1 and 0.2g/kg/d. Control adopted the same age and background C57BL/6J mice. The animals were administered intragastrically by the drug or water from 4 to 10 month old. For untreated 10 month APP Tg mice, TSG low dose and middle dose were administrated to them from 10 to 16 month old. APP695 wild-type transfected SH-SY5Y neuroblastoma cell (SH-SY5Y APP695) was incubated with TSG at dose of 1,10 and 100mg/ml for 24 hours. Control adopted the untransfected SH-SY5Y neuroblastoma cells. The mRNA expression was measured by gene chips (80s mice full sequence gene chips, more than 8,000 genes). The protein expression was detected by western-blotting methods. Results: Several components (PKC, ERK, p70S6K) in Mitogen activated protein kinases (MAPKs) signal transduction pathway were abnormally expressed and activated both in APP Tg mice and SH-SY5Y APP695 cells. The changes of MAPKs were related with the different age of APP transgenic mice. TSG improved the MAPKs signal transduction pathway and maintain the survival and normal function of neural cells at the AD-like animal and cellular models. Conclusions: TSG not only prevents the occurrence of abnormal lesion of MAPKs signal transduction pathway in early stage of AD-like model but also reverse the abnormal lesion in late stage of AD-like model. TSG indicate effectiveness in neural protection on several targets relating to AD, so it would be benefit for the treatment of AD and other neurodegenerative diseases. Our research finds a possible therapeutic application to neurodegenerative disease, as well as provides new strategies for prevention and treatment of AD.
• Zhao, L., Yao, J., Mao, Z., Chen, S., Wang, Y., & Brinton, R. D. (2011). 17 beta-Estradiol regulates insulin-degrading enzyme expression via an ER beta/PI3-K pathway in hippocampus: Relevance to Alzheimer's prevention. NEUROBIOLOGY OF AGING, 32(11), 1949-1963.
• Zheng, B., Wang, J. M., Sun, C., Stockmeier, C. A., Smeyne, R. J., Paul, I. A., Pani, A. K., Kyle, P. B., Jiao, Y., Hou, X., Henry, S., Farley, J. M., Brinton, R. D., Bigler, S. A., & Adeosun, S. O. (2011). The impact of a neurogenic agent, allopregnanolone, in rodent models of Alzheimer's and Parkinson's disease. Alzheimers & Dementia, 7(4), S667-S667. doi:10.1016/j.jalz.2011.05.1918
• Henderson, V. W., & Brinton, R. D. (2010). Menopause and mitochondria: Windows into Estrogen effects on Alzheimer's disease risk and therapy. NEUROENDOCRINOLOGY: PATHOLOGICAL SITUATIONS AND DISEASES, 182, 77-96.
• Liu, L., Zhao, L., She, H., Chen, S., Wang, J. M., Wong, C., McClure, K., Sitruk-Ware, R., & Brinton, R. D. (2010). Clinically Relevant Progestins Regulate Neurogenic and Neuroprotective Responses in Vitro and in Vivo. ENDOCRINOLOGY, 151(12), 5782-5794.
• Wang, J. M., Singh, C., Liu, L., Irwin, R. W., Chen, S., Chung, E. J., Thompson, R. F., & Brinton, R. D. (2010). Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 107(14), 6498-6503.
• Wang, J. M., Thompson, R. F., Singh, C., Liu, L., Irwin, R. W., Chung, E. J., Chen, S., & Brinton, R. D. (2010). Correction for Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 107(24).
• Yao, J., Hamilton, R. T., Cadenas, E., & Brinton, R. D. (2010). Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1800(10), 1121-1126.
• Yao, J., Hamilton, R. T., Cadenas, E., & Brinton, R. D. (2010). Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence. Biochimica et biophysica acta, 1800(10), 1121-6.
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  We have previously demonstrated that mitochondrial bioenergetic deficits precede Alzheimer's pathology in the female triple transgenic Alzheimer's (3xTgAD) mouse model. Herein, we sought to determine the impact of reproductive senescence on mitochondrial function in the normal non-transgenic (nonTg) and 3xTgAD female mouse model of AD.
• Yao, J., Irwin, R. W., Chen, S., & Brinton, R. D. (2010). Deficits in mitochondrial bioenergetics and mitochondrial beta-amyloid deposition in brain are associated with reproductive senescence and loss of ovarian hormones: Prevention by estradiol. Alzheimers & Dementia, 6(4), S559-S559. doi:10.1016/j.jalz.2010.05.1907
• Yao, J., Wang, J. M., Thompson, R. F., Singh, C., Liu, L., Irwin, R. W., Henry, S., Chen, S., & Brinton, R. D. (2010). Allopregnanolone promotes neurogenesis, restores cognitive function and reduces Alzheimer's pathology in adult triple transgenic Alzheimer's mice: Preclinical development and formulation. Alzheimers & Dementia, 6(4), S560-S560. doi:10.1016/j.jalz.2010.05.1911
• Asthana, S., Brinton, R. D., Henderson, V. W., McEwen, B. S., Morrison, J. H., & Schmidt, P. J. (2009). Frontiers proposal. National Institute on Aging "bench to bedside: estrogen as a case study". AGE, 31(3), 199-210.
• Brinton, R. D., & Brinton, R. D. (2009). Estrogen-induced plasticity from cells to circuits: predictions for cognitive function.. Trends in pharmacological sciences, 30(4), 212-22. doi:10.1016/j.tips.2008.12.006
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  Controversy regarding estrogen action in the brain remains at the forefront of basic, translational and clinical science for women's health. Here, I provide an integrative analysis of estrogen-inducible plasticity and posit it as a strategy for predicting cognitive domains affected by estrogen in addition to sources of variability. Estrogen enhancement of plasticity is evidenced by increases in neurogenesis, neural network connectivity and synaptic transmission. In parallel, estrogen increases glucose transport, aerobic glycolysis and mitochondrial function to provide the ATP necessary to sustain increased energetic demand. The pattern of plasticity predicts that estrogen would preferentially affect cognitive tasks of greater complexity, temporal demand and associative challenge. Thus, estrogen deprivation should be associated with decrements in these functions. Estrogen regulation of plasticity and bioenergetics provides a framework for predicting estrogen-dependent cognitive functions while also identifying sources of variability and potential biomarkers for identifying women appropriate for hormone therapy.
• Liu, L., Wang, J., Zhao, L., Nilsen, J., McClure, K., Wong, K., & Brinton, R. D. (2009). Progesterone Increases Rat Neural Progenitor Cell Cycle Gene Expression and Proliferation Via Extracellularly Regulated Kinase and Progesterone Receptor Membrane Components 1 and 2. ENDOCRINOLOGY, 150(7), 3186-3196.
• Schmidt, P., Morrison, J. H., Gore, A. C., & Brinton, R. D. (2009). Reproductive Aging of Females: Neural Systems. Hormones, brain and behavior, 68, 2199-2224. doi:10.1016/b978-008088783-8.00068-1
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  Although reproductive senescence is defined by oocyte depletion, reproductive aging results from the complex interplay of age-dependent endocrine changes and the hypothalamic–pituitary–gonadal axis. In women, the transition from a reproductive life stage to postmenopausal life stage is a dynamic process that occurs in stages that have both discrete endocrine events and variable parameters. The contributions from basic neuroscience in cells and animal models and from clinical trials of hormone therapy during menopause have dramatically enhanced the current understanding of reproductive aging in the brain. Here, the state of research of reproductive aging in the hypothalamus, hippocampus, and prefrontal cortex as well as the current understanding of hormone therapy are described with regard to the brain, cognition, and mood function throughout the menopause transition. As the worldwide population ages and more than 1.2 billion women become 50 years old or older in 2030, understanding of the complexity of these hormone–brain circuits and translating those insights into healthy aging strategies will become ever more critical.
• Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., & Brinton, R. D. (2009). Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 106(34), 14670-14675.
• Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., & Brinton, R. D. (2009). Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 106(34), 14670-5.
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  Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (Abeta) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of Abeta binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.
• Zhao, L., Mao, Z., & Brinton, R. D. (2009). A Select Combination of Clinically Relevant Phytoestrogens Enhances Estrogen Receptor beta-Binding Selectivity and Neuroprotective Activities in Vitro and in Vivo. ENDOCRINOLOGY, 150(2), 770-783.
• Brinton, R. D. (2008). Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease.. Advanced drug delivery reviews, 60(13-14), 1504-11. doi:10.1016/j.addr.2008.06.003
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  Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis and citric acid cycle-driven oxidative phosphorylation and ATP generation. Data derived from experimental and clinical paradigms investigating estrogen intervention in healthy systems and prior to neurodegenerative insult indicate enhanced neural defense and survival through maintenance of calcium homeostasis, enhanced glycolysis coupled to the citric acid cycle (aerobic glycolysis), sustained and enhanced mitochondrial function, protection against free radical damage, efficient cholesterol trafficking and beta amyloid clearance. The convergence of E(2) mechanisms of action onto mitochondrial is also a potential point of vulnerability when activated in a degenerating neural system and could exacerbate the degenerative processes through increased load on dysregulated calcium homeostasis. The data indicate that as the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neuronal survival and neurological function. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the basic to clinical domains of scientific inquiry and on which to predict future applications of estrogen and hormone therapeutic interventions sustain neurological health and to prevent age-associated neurodegenerative diseases such as Alzheimer's. Overall, E(2) promotes the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer's.
• Brinton, R. D. (2008). The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications.. Trends in neurosciences, 31(10), 529-37. doi:10.1016/j.tins.2008.07.003
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  The 'healthy cell bias of estrogen action' hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance aerobic glycolysis coupled to the citric acid cycle, mitochondrial respiration and ATP generation. Convergence of estrogen-induced signaling onto mitochondria is also a point of vulnerability when activated in diseased neurons which exacerbates degeneration through increased load on dysregulated calcium homeostasis. As the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess disparities in outcomes across basic and clinical science and on which to predict outcomes of estrogen interventions for sustaining neurological health and preventing age-associated neurodegenerative diseases such as Alzheimer's.
• Brinton, R. D., Thompson, R. F., Foy, M. R., Baudry, M., Wang, J., Finch, C. E., Morgan, T. E., Pike, C. J., Mack, W. J., Stanczyk, F. Z., & Nilsen, J. (2008). Progesterone receptors: Form and function in brain. FRONTIERS IN NEUROENDOCRINOLOGY, 29(2), 313-339.
• Foy, M. R., Baudry, M., Brinton, R. D., & Thompson, R. F. (2008). Estrogen and Hippocampal Plasticity in Rodent Models. JOURNAL OF ALZHEIMERS DISEASE, 15(4), 589-603.
• Irwin, R. W., Yao, J., Hamilton, R. T., Cadenas, E., Brinton, R. D., & Nilsen, J. (2008). Progesterone and estrogen regulate oxidative metabolism in brain mitochondria. ENDOCRINOLOGY, 149(6), 3167-3175.
• Wang, J. M., & Brinton, R. D. (2008). Allopregnanolone-induced rise in intracellular calcium in embryonic hippocampal neurons parallels their proliferative potential. BMC NEUROSCIENCE, 9.
• Wang, J. M., Liu, L., & Brinton, R. D. (2008). Estradiol-17 beta-induced human neural progenitor cell proliferation is mediated by an estrogen receptor beta-phosphorylated extracellularly regulated kinase pathway. ENDOCRINOLOGY, 149(1), 208-218.
• Wang, J. M., Liu, L., Irwin, R. W., Chen, S., & Brinton, R. D. (2008). Regenerative potential of allopregnanolone. BRAIN RESEARCH REVIEWS, 57(2), 398-409.
• Brinton, R. D. (2007). Building a neuroscience legacy.. The Journal of neuroscience : the official journal of the Society for Neuroscience, 27(42), 11163-6. doi:10.1523/jneurosci.4208-07.2007
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  The greatest chance of vanquishing neurological disease lies not with what is on the bench, but with who is working at the bench . Although great discoveries are aided by technological advance, not a single great discovery was ever made by a technology. Discovery comes from a scientist testing a
• Nilsen, J., Irwin, R. W., Gallaher, T. K., & Brinton, R. D. (2007). Estradiol In Vivo regulation of brain mitochondrial proteome. JOURNAL OF NEUROSCIENCE, 27(51), 14069-14077.
• Soussou, W. V., Yoon, G. J., Brinton, R. D., & Berger, T. W. (2007). Neuronal network morphology and electrophysiology of hippocampal neurons cultured on surface-treated multielectrode arrays. IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, 54(7), 1309-1320.
• Wang, J. M., Irwin, R. W., Liu, L., Chen, S., & Brinton, R. D. (2007). Regeneration in a degenerating brain: Potential of allopregnanolone as a neuroregenerative agent. CURRENT ALZHEIMER RESEARCH, 4(5), 510-517.
• Wang, J. M., Seligman, E., Liu, L., Irwin, R. W., Chung, E. J., Chen, S., & Brinton, R. D. (2007). P-076: Estrogen receptor-selective ligands regulate ApoE expression and neurogenesis in 3xTgAD mouse hippocampus. Alzheimers & Dementia, 3(3), S123-S123. doi:10.1016/j.jalz.2007.04.329
• Wang, J. M., Thompson, R. F., Singh, C., Liu, L., Irwin, R. W., Chen, S., & Brinton, R. D. (2007). O2-04-07: Allopregnanolone reverses the neurogenic and cognitive deficits of triple transgenic Alzheimer mice. Alzheimers & Dementia, 3(3), S194-S194. doi:10.1016/j.jalz.2007.04.302
• Yao, J., Nilsen, J., Irwin, R. W., & Brinton, R. D. (2007). AbstractPosterP-073: Prevention of Alzheimer’s pathology: Estrogen targeting of mitochondrial function. Alzheimers & Dementia, 3(3), S122-S122. doi:10.1016/j.jalz.2007.04.326
• Zhao, L., & Brinton, R. D. (2007). Estrogen receptor alpha and beta differentially regulate intracellular Ca2+ dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons. BRAIN RESEARCH, 1172, 48-59.
• Zhao, L., & Brinton, R. D. (2007). P-078: Preclinical investigation of combined use of select ERβ-selective phytoserms as a potential estrogen alternative strategy for prevention of Alzheimer’s disease in women. Alzheimers & Dementia, 3(3), S123-S124. doi:10.1016/j.jalz.2007.04.331
• Zhao, L., & Brinton, R. D. (2007). WHI and WHIMS follow-up and human studies of soy isoflavones on cognition.. Expert review of neurotherapeutics, 7(11), 1549-64. doi:10.1586/14737175.7.11.1549
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  Recent follow-up analyses of the previous findings from the Women's Health Initiative and the Women's Health Initiative Memory Study confirmed some health benefits of estrogen-containing hormone therapy (HT) in women within 10 years from the onset of menopause. However, the potential risks associated with long-term administration of HT, such as breast cancer and stroke, remain a concern for therapy recipients, underlying the need for an alternative treatment that is functionally equivalent but with a greater safety profile. Owing to their structural and functional resemblance to mammalian estrogens and lack of evident adverse effects, research interest in plant-derived phytoestrogens has increased in the past decade. While multiple health-promoting benefits of phytoestrogens have been proposed from basic science, the clinical data remain inconclusive. This review provides a comparative analysis of human studies on the effects of soy-based isoflavones on cognition. Of the eight studies published in 2000-2007, seven were conducted in postmenopausal women, four of which revealed a positive impact of isoflavones on cognitive function. Multiple factors could have contributed to the discrepant outcomes across studies, such as variation in the composition of phytoestrogen interventions and the heterogeneous characteristics of the study population. Thus, a well-designed clinical study based on a standardized stable formulation in a well-characterized study population is required in order to reach a clinical consensus. A formulation composed of select estrogen receptor beta-selective phytoestrogens with a rationally designed composition would avoid the potential antagonism present in a mixture and thus enhance therapeutic efficacy. In addition, inclusion of equol in a study formulation offers a potential synergistic effect from equol in both equol-producing and nonproducing individuals, as well as added benefits for men. With respect to the design of study population, a clinically consistent effect could potentially be achieved by stratifying populations based on genotype, age, hormonal history and even diets. Development of an effective phytoestrogen formulation would benefit both women and men to prevent or treat hormone-dependent conditions and, most of all, to improve neurological health and reduce the risk of Alzheimer's disease.
• Zhao, L., Jin, C., Mao, Z., Gopinathan, M. B., Rehder, K., & Brinton, R. D. (2007). Design, synthesis, and Estrogenic activity of a novel estrogen receptor modulator - A hybrid structure of 17 beta-estradiol and vitamin E in hippocampal neurons. JOURNAL OF MEDICINAL CHEMISTRY, 50(18), 4471-4481.
• Brewer, G. J., Reichensperger, J. D., & Brinton, R. D. (2006). Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons. NEUROBIOLOGY OF AGING, 27(2), 306-317.
• Brewer, G. J., Reichensperger, J. D., & Brinton, R. D. (2006). Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons. Neurobiology of aging, 27(2), 306-17.
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  To determine the impact of aging and 17beta-estradiol on neuronal Ca2+ homeostasis, intracellular Fura-2 Ca2+-imaging was conducted during 20-pulses of glutamate in hippocampal neurons cultured from embryonic (E18), middle-age (10 months) and old (24 months) rat brain. Marked age-related differences in intracellular Ca2+ ([Ca2+]i) homeostasis and striking regulation by 17beta-estradiol were seen. Embryonic neurons exhibited the greatest capacity to regulate Ca2+ homeostasis followed by middle-age neurons. In old neurons, the first peak [Ca2+]i was substantially greater than at other ages and the return to baseline Ca2+ rapidly dysregulated with an inability to restore [Ca2+]i following the first glutamate pulse which persisted throughout the 20 pulses. 17beta-Estradiol pretreatment of old neurons profoundly attenuated the peak [Ca2+]i rise and delayed the age-associated dysregulation of baseline [Ca2+]i, normalizing responses to those of middle-age neurons treated with estradiol. The efficacy of 17beta-estradiol extended below 10 pg/ml with full protection against toxicity from glutamate and Abeta (1-40). These results demonstrate age-associated dysregulation of [Ca2+]i homeostasis which was largely prevented by 17beta-estradiol with implications for estrogen/hormone therapy.
• Chen, S., Nilsen, J., & Brinton, R. D. (2006). Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: Therapeutic implications. ENDOCRINOLOGY, 147(11), 5303-5313.
• Kim, M. T., Soussou, W., Gholmieh, G., Ahuja, A., Tanguay, A., Berger, T. W., & Brinton, R. D. (2006). 17 beta-estradiol potentiates field excitatory postsynaptic potentials within each subfield of the hippocampus with greatest potentiation of the associational/commissural afferents of CA3. NEUROSCIENCE, 141(1), 391-406.
• Mannella, P., & Brinton, R. D. (2006). Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: A unified mechanism of estrogen action. JOURNAL OF NEUROSCIENCE, 26(37), 9439-9447.
• Morrison, J. H., Brinton, R. D., Schmidt, P. J., & Gore, A. C. (2006). Estrogen, menopause, and the aging brain: How basic neuroscience can inform hormone therapy in women. JOURNAL OF NEUROSCIENCE, 26(41), 10332-10348.
• Nilsen, J., Chen, S., Irwin, R. W., Iwamoto, S., & Brinton, R. D. (2006). Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC NEUROSCIENCE, 7.
• Nilsen, J., Irwin, R. W., & Brinton, R. D. (2006). P4-390: Brain mitochondria as therapeutic target for the prevention of Alzheimers pathology. Alzheimers & Dementia, 2(3), S632-S633. doi:10.1016/j.jalz.2006.05.2131
• Nilsen, J., Morales, A., & Brinton, R. D. (2006). Medroxyprogesterone acetate exacerbates glutamate excitotoxicity. GYNECOLOGICAL ENDOCRINOLOGY, 22(7), 355-361.
• Wang, J. M., & Brinton, R. D. (2006). Preclinical analyses of the therapeutic potential of allopregnanolone to promote neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer's disease.. Current Alzheimer research, 3(1), 11-7. doi:10.2174/156720506775697160
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  Herein, we present data to support a preclinical proof of concept for the therapeutic potential of allopregnanolone to promote neurogenesis. Our recent work has demonstrated that the neuroactive progesterone metabolite, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), (APalpha) induced, in a dose dependent manner, a significant increase in proliferation of neuroprogenitor cells (NPCs) derived from the rat hippocampus and human neural stem cells (hNSM) derived from the cerebral cortex [1]. Proliferative efficacy was determined by incorporation of BrdU and (3)H-thymidine, FACS analysis of MuLV-GFP-labeled mitotic NPCs and quantification of total cell number. Allopregnanolone-induced proliferation was isomer and steroid specific, in that the stereoisomer 3beta-hydroxy-5beta-pregnan-20-one and related steroids did not increase (3)H-thymidine uptake. Immunofluorescent analyses for the NPC markers, nestin and Tuj1, indicated that newly formed cells were of neuronal lineage. Furthermore, microarray analysis of cell cycle genes and real time RT-PCR and western blot validation revealed that allopregnanolone increased the expression of genes which promote mitosis and inhibited the expression of genes that repress cell proliferation. Allopregnanolone-induced proliferation was antagonized by the voltage gated L-type calcium channel blocker nifedipine consistent with the finding that allopregnanolone induces a rapid increase in intracellular calcium in hippocampal neurons via a GABA type A receptor activated L-type calcium channel. Preliminary in vivo data indicate that APalpha for 24 hrs significantly increased neurogenesis in dentate gyrus, as determined by unbiased stereological analysis of BrdU positive cells, of 3-month-old male triple transgenic Alzheimer's disease mice. The in vitro and in vivo neurogenic properties of APalpha coupled with a low molecular weight, easy penetration of the blood brain barrier and lack of toxicity, are key elements required for developing APalpha as a neurogenic / regenerative therapeutic for restoration of neurons in victims of Alzheimer's disease.
• Wang, J. M., & Brinton, R. D. (2006). Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer's disease: allopregnanolone as a proof of concept neurogenic agent.. Current Alzheimer research, 3(3), 185-90. doi:10.2174/156720506777632817
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  A major challenge not yet addressed by current therapeutic interventions for Alzheimer's disease (AD) is the regeneration of lost neurons and neural circuitry to restore cognitive function. Therapies that lead to cessation of the degenerative process still leave the brain riddled with deteriorated neural circuits and reduced neuron number. The discovery of neurogenesis in the adult brain and the regenerative potential of neural stem cells holds the promise for restoration of neural populations and regeneration of neural circuits necessary for cerebral function. While the regenerative potential of neural stem cells is great, so too is the challenge of delivering neural stem cells to the brain. Basic science analyses and human trials indicate that constituents of microenvironments within the brain determine the neurogenic potential, phenotypic differentiation of neural stem cells and magnitude of the neural stem cell pool. Multiple analyses have documented that dentate neurogenesis is regulated by multiple growth factors which are abundant during development and which dramatically decline with age. While the cause(s) of age-associated decline in neurogenesis remains to be fully determined, loss in growth factors, FGF-2, IGF-1 and VEGF, in the microenvironment of the subgranular zone (SGZ) are prime contributors to the reduced neurogenic potential. The decline in dentate neurogenesis can be observed as early as middle age. In the aged and AD brain, both the pool of neural stem cells and their proliferative potential are markedly diminished. In parallel, the level of potential regenerative factors is diminished in the brains of Alzheimer's patients compared to age-matched controls. Our efforts have been directed towards discovery and development of small, blood brain barrier penetrant molecules to promote endogenous proliferation of neural stem cells within the brain. These endeavors have led to the discovery that the neurosteroid alloprognanolone (APalpha) is a potent and highly efficacious proliferative agent in vitro and in vivo of both rodent and human neural stem cells. Results of our in vitro studies coupled with our more recent analyses in the triple transgenic mouse model of AD suggest that APalpha is a promising strategy for promoting neurogenesis in the aged brain and potentially for restoration of neuronal populations in brains recovering from neurodegenerative disease or injury. A brief overview of issues impacting the therapeutic potential of neurogenesis and the factors used to promote neurogenesis in the aging and degenerating brain is presented. Also included is a review of our current research into the neurogenic potential of the small molecule, blood brain barrier penetrating, neurosteroid allopregnanolone (APalpha).
• Wang, J. M., Irwin, R. W., & Brinton, R. D. (2006). Activation of estrogen receptor alpha increases and estrogen receptor beta decreases apolipoprotein E expression in hippocampus in vitro and in vivo. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 103(45), 16983-16988.
• Wang, J. M., Irwin, R., & Brinton, R. D. (2006). P3-202: Activation of estrogen receptor α increases and estrogen receptor β decreases apolipoprotein E expression in hippocampus in vitro and in vivo. Alzheimer's & Dementia, 2, S435-S435. doi:10.1016/j.jalz.2006.05.1471
• Wu, T., Wang, J. M., Liu, L., Irwin, R. W., Chen, S., & Brinton, R. D. (2006). P4-350: Promotion of neurogenesis in the triple transgenic Alzheimer’s mouse dentate gyrus and subventricular zone by the neurosteroid allopregnanolone. Alzheimers & Dementia, 2(3), S620-S620. doi:10.1016/j.jalz.2006.05.2091
• Zhao, L. Q., & Brinton, R. D. (2006). Select estrogens within the complex formulation of conjugated equine estrogens (Premarin (R)) are protective against neurodegenerative insults: Implications for a composition of estrogen therapy to promote neuronal function and prevent Alzheimer's disease. BMC NEUROSCIENCE, 7.
• Zhao, L., & Brinton, R. D. (2006). AbstractPoster presentation: Wednesday posterP4-414: Impact of ERβ-selective phytoserm formulations on neuronal survival and morphogenesis: Promise as an estrogen alternative replacement therapy for prevention of Alzheimer’s disease and related neurological disorders. Alzheimers & Dementia, 2(3), S639-S640. doi:10.1016/j.jalz.2006.05.2156
• Zhao, L., O'Neill, K., & Brinton, R. D. (2006). Estrogenic agonist activity of ICI 182,780 (Faslodex) in hippocampal neurons: Implications for basic science understanding of estrogen signaling and development of estrogen modulators with a dual therapeutic profile. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 319(3), 1124-1132.
• Brinton, R. D. (2005). Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action.. Annals of the New York Academy of Sciences, 1052(1), 57-74. doi:10.1196/annals.1347.005
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  The profound disparities between the largely positive basic science findings of gonadal steroid action in brain and the adverse outcomes of recent hormone therapy clinical trials in women who are either aged postmenopausal or postmenopausal with Alzheimer's disease have led to an intense reassessment of gonadal hormone action and the model systems used in basic and clinical science. The power of model systems is their predictive validity for a target population--in this case, menopausal women considering the health benefits and risks of hormone therapy. Analysis of the model systems used across the basic to clinical research continuum separate into two broad classes: those that use prevention interventions in healthy organisms and those that use hormone interventions in organisms with compromised neurological function. Basic science analyses that led to elucidation of the neurotrophic and neuroprotective effects of estrogen and the underlying mechanisms of action typically used a prevention-based experimental paradigm. This paradigm relies on healthy neurons/brains/animals/humans as the starting foundation followed by exposure to estrogen/hormone followed by exposure to neurodegenerative insult. The prevention paradigm in basic science analyses parallels the analyses of Sherwin and colleagues (Psychoneuroendocrinology 13: 345-357, 1988), who investigated the cognitive impact of estrogen therapy in women with surgical- or pharmacological-induced menopause. Observational retrospective and prospective studies are also consistent with the healthy cell bias of estrogen action and a prevention paradigm of estrogen or hormone therapy intervention. For the most part, the epidemiological observational data indicate reduction in the risk of Alzheimer's disease in women who began estrogen or hormone therapy at the time of the menopause. In contrast, studies that fall within the second class, hormone intervention in organisms with compromised neurological function--that is, a treatment paradigm--exhibit a mixed profile. In a randomized double-blind clinical trial of estrogen therapy in a cohort of women aged 72 or more years and diagnosed with Alzheimer's disease, estrogen therapy resulted in a modest benefit in the short term (2 months) and adverse progression of disease in the long term (12 months). In the Women's Health Initiative Memory Study (WHIMS) cohort of women 65 or more years of age, with no indicators of neurological disease but with variable health status, estrogen and hormone therapy for 5 years increased the risk of developing Alzheimer's disease. These data would suggest that as the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neurological function and survival. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. Based on these and other data, a hypothesis of a healthy cell bias of gonadal hormone action is put forth. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the domains of scientific inquiry and to access future applications of estrogen and hormone therapeutic interventions.
• Chen, S., & Brinton, R. D. (2005). In vitro model system to predict efficacy of estrogens to prevent versus treat Alzheimer’s disease. Alzheimers & Dementia, 1(1), S75-S75. doi:10.1016/j.jalz.2005.06.268
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  activity in such isolated secretory vesicles was subjected to extensive purification and identified by peptide sequencing. Conclusions: Results demonstrated two distinct proteolytic pathways consisting of (a) cathepsin B cleavage of the Abeta-secretase site, and (b) cathepsin L cleavage adjacent to the Abeta-secretase site at Lys-Met, followed by methionine aminopeptidase. Colocalization of cathepsins B and L with Abeta peptides in regulated secretory vesicles was illustrated by electron microscopy. Efficient cleavage of the wild-type Abeta-secretase site by cathepsins B and L was illustrated by kcat/Km kinetic constants of 31,700 and 8,620 M-1s-1, respectively, with little cleavage of the Swedish mutant Abetasecretase site. Since the majority of Alzheimer’s patients express wild-type APP, proteases with specificity for the normal Abeta-secretase site are relevant to the disease. In contrast, BACE 1 shows poor catalytic efficiency for the wild-type Abeta-secretase site. Significantly, the selective cathepsin B inhibitor CA074 blocked Abeta production in regulated secretory vesicles isolated from neuronal chromaffin cells. These findings implicate the cysteine proteases cathepsin B and cathepsin L in the regulated secretory pathway as important new therapeutic targets for protease inhibitor drugs to Abeta of Alzheimer’s disease.
• Nilsen, J., Deng, J., & Brinton, R. D. (2005). Clinical progestins and their efficacy to promote neuron survival and neurogenesis. Alzheimers & Dementia, 1(1), S69-S69. doi:10.1016/j.jalz.2005.06.251
• Nilsen, J., Deng, J., & Brinton, R. D. (2005). Impact of clinically relevant progestins on the neural effects of estradiol and the signaling pathways involved.. Drug news & perspectives, 18(9), 545-53. doi:10.1358/dnp.2005.18.9.948450
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  The natural ovarian hormone progesterone functions as an effective neuroprotective agent. However, in its native state it is not an efficient therapeutic compound because of its poor bioavailability. Thus, for practical therapeutic usage it became necessary to develop orally active progestogens for use in hormone therapy. We have shown that not all progestogens are equal in their ability to modulate neuronal survival and markers of neuronal plasticity. Thus, one cannot assume that all hormone therapies will perform the same, and it is crucial to determine the neural effects and interactions with estradiol of synthetic progestins used in place of natural progesterone. We have analyzed a number of clinically relevant progestins for neuroprotective efficacy. These in vitro analyses of neuroprotective efficacy could serve as a predictive index of clinical efficacy for progestins to protect against degenerative insults that lead to Alzheimer's disease. To aid in such therapeutic development, we determined the chemical structural features that predict progestin efficacy in the brain and showed that binding affinity does not predict neuroprotective efficacy or the direction of effect and thus cannot be used as an indicator of neurological benefit. In contrast, there was a set of common features of ligand-receptor interactions that are correlative and hopefully predictive of neuroprotective efficacy. Elucidation of the sites and targets of progestogen action should have a clear impact on both the use of hormone therapy for the prevention of neurodegenerative disease and the future design of target-specific hormone therapy formulations.
• Nilsen, J., Masri, R., Irwin, R. W., & Brinton, R. D. (2005). Estrogen regulation of mitochondrial function: Target for therapeutics to prevent Alzheimer’s disease. Alzheimers & Dementia, 1(1), S71-S72. doi:10.1016/j.jalz.2005.06.258
• Vazquez, M. C., Swerdlow, R., Smigrodzki, R. M., Reddy, P. H., Pugh, M., Nilsen, J., Lowell, J., Leski, M., Khan, S. M., Fagan, T., David, D. C., & Brinton, R. D. (2005). Alzheimer Research Forum Live Discussion: A "Mitochondrial Cascade Hypothesis" for sporadic Alzheimer's disease. Journal of Alzheimer's Disease, 8(3), 311-315. doi:10.3233/jad-2005-8310
• Wang, J. M., & Brinton, R. D. (2005). Differential regulation of apolipoprotein E expression by estrogen receptor A and B isoform-selective ligands: Estrogen receptor selective hormone therapy. Alzheimers & Dementia, 1(1), S68-S68. doi:10.1016/j.jalz.2005.06.248
• Wang, J. M., Johnston, P. B., Ball, B. G., & Brinton, R. D. (2005). The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. JOURNAL OF NEUROSCIENCE, 25(19), 4706-4718.
• Wu, T. W., Wang, J. M., Chen, S., & Brinton, R. D. (2005). 17 beta-Estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-amp response element binding protein signal pathway and Bcl-2 expression in rat hippocampal neurons: A potential initiation mechanism for estrogen-induced neuroprotection. NEUROSCIENCE, 135(1), 59-72.
• Zhao, L. Q., & Brinton, R. D. (2005). Structure-based virtual screening for plant-based ER beta-selective ligands as potential preventative therapy against age-related neurodegenerative diseases. JOURNAL OF MEDICINAL CHEMISTRY, 48(10), 3463-3466.
• Zhao, L. Q., O'Neill, K., & Brinton, R. D. (2005). Selective estrogen receptor modulators (SERMs) for the brain: Current status and remaining challenges for developing NeuroSERMs. BRAIN RESEARCH REVIEWS, 49(3), 472-493.
• Zhao, L., & Brinton, R. D. (2005). Estrogen receptor beta selective ligands for prevention of neurodegeneration: From in silico screening to at bench bioanalysis. Alzheimers & Dementia, 1(1), S67-S67. doi:10.1016/j.jalz.2005.06.380
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  of A 12-28P in AD Tg model mice. Methods: Female APP/ PS1 Tg AD mice were treated with A 12-28P (1mg of peptide or placebo administered intraperitoneally) for five months starting from the age of two months, which is prior to the onset of detectable brain amyloid deposits. Conclusions: Treatment with A 12-28P resulted in a significant reduction of A load: 51.6% in the neocortex, 40.0% in the hippocampus, and 49.2% in the cingulate/retropslenial cortex (p 0.01). Fibrillar A , detected by Thioflavin-S staining, was reduced by 21.9%, 24.7%, and 28.9%, respectively (p 0.05). Levels of formic acid extracted A 1-40 and A 1-42 were decreased on ELISA measurements by 42.5% and 29.9%, respectively (p 0.01). No signs of toxicity or any autoimmune reaction were observed in treated animals. These results demonstrate that pharmacological blocking of the apoE/A interaction may be used to prevent A deposition in AD patients.
• Zhao, L., & Brinton, R. D. (2005). Estrogen receptor β as a therapeutic target for promoting neurogenesis and preventing neurodegeneration. Drug Development Research, 66(2), 103-117. doi:10.1002/ddr.20049
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  Both estrogen receptor (ER) subtypes, ERα and ERβ, are expressed throughout the brain of both rodents and humans. Analyses from our laboratory and others reveal that both ERα and ERβ can contribute to estrogen-induced protection against neurodegenerative insults. ERβ plays a key role in regulating brain development and estrogen-induced promotion of neurogenesis and memory. These findings suggest that targeting ERβ could generate safe and effective therapeutics to promote neuronal defense mechanisms and to maintain cognitive function, while simultaneously reducing adverse effects in reproductive organs such as breast and uterus. A number of naturally occurring ERβ selective phytoestrogens have been identified and multiple structurally diverse ERβ selective ligands have been synthesized. A comparison of the models of complexes between selective agonists and either ERα or ERβ reveals that two variant amino acid residues in the ligand binding site, Leu384 and Met421 in ERα, which are replaced with Met336 and Ile373, respectively, in ERβ, are the key molecular constituents underlying the binding of selective ligands to either ER subtype. Development of an ERβ brain-selective estrogen receptor modulator, in particular a natural source formulation, has great potential benefit for peri- and post-menopausal women who face age-associated cognitive decline and neurodegeneration. In addition, an ERβ selective formulation might promote neuronal defense mechanisms and cognition in men, while reducing the risk of prostate cancer. Drug Dev. Res. 66:103–117, 2006. © 2006 Wiley-Liss, Inc.
• Zhao, L., Chen, S., Wang, J. M., & Brinton, R. D. (2005). 17 beta-estradiol induces Ca2+ influx, dendritic and nuclear Ca2+ rise and subsequent cyclic amp response element-binding protein activation in hippocampal neurons: A potential initiation mechanism for estrogen neurotrophism. NEUROSCIENCE, 132(2), 299-311.
• Brinton, R. D. (2004). Impact of estrogen therapy on Alzheimer's disease: a fork in the road?. CNS drugs, 18(7), 405-22. doi:10.2165/00023210-200418070-00001
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  The results of recent clinical studies have challenged our previously held view that estrogen therapy promotes neurological health and prevents or ameliorates Alzheimer's disease. A major question emerging from these studies is: how can there be such disparity between the basic science and epidemiological data that show that estrogen can protect neurons against degenerative insults and reduce the risk of Alzheimer's disease and the recent data (from the Women's Health Initiative Memory Study [WHIMS] trial and the trial of estrogen treatment for Alzheimer's disease), which show that hormone replacement therapy (HRT) showed no benefit and even a potential deleterious effect? Which set of data is correct? The proposition put forth in this review is that both sets of data are correct and that two major factors determine the efficacy of estrogen or HRT. First is the time at which estrogen therapy is initiated. The data indicate that initiation of therapy early in menopause and when neurons are in a healthy state, reduces the risk of Alzheimer's disease; whereas, estrogen therapy initiated after the disease has developed or decades following menopause is without benefit. Second, estrogen therapy is not the same as HRT and the type of progestogen used determines the outcome of the therapeutic intervention. Insights into the mechanisms of action of estrogen and progestogen in the brain provide a framework for understanding the paradox of the benefit of estrogen in the prevention of Alzheimer's disease versus the lack of benefit in treatment trials and in trials when HRT is instituted many years after menopause. Based on estrogen-inducible mechanisms, which have been elucidated in healthy neuron model systems, it would be predicted that estrogen therapy could be highly effective in preventing neurodegenerative disease by promoting neuronal defence and memory mechanisms. The mechanisms of action of estrogen also predict that estrogen therapy would be an ineffective strategy for reversing the pathology of Alzheimer's disease. In summary, the time at which estrogen therapy is initiated, the neurological status of the brain at the time of estrogen therapy initiation and the type of progestogen used all contribute to the efficacy of estrogen in preventing neurodegenerative disease and to sustaining neurological health and function. An estrogen advantage hypothesis is put forth that provides a unifying mechanism of estrogen action with implications for both the benefits and risks of estrogen therapy.
• Brinton, R. D. (2004). Requirements of a brain selective estrogen: advances and remaining challenges for developing a NeuroSERM.. Journal of Alzheimer's disease : JAD, 6(6 Suppl), S27-35. doi:10.3233/jad-2004-6s607
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  Our goal is to develop therapeutic agents that prevent age-associated neurodegenerative disease such as Alzheimer's. To achieve this goal, we are building on extensive knowledge regarding mechanisms of estrogen action in brain and the epidemiological human data indicating that estrogen/hormone therapy reduces the risk of developing Alzheimer's disease when administered at the time of the menopause and continued over several to many years. The mechanisms of estrogen action in neurons provides a systematic mechanistic rationale for determining why estrogen therapy is efficacious for prevention of Alzheimer's disease and why it is not efficacious for long-term treatment of the disease. Our preclinical research plan is a hybrid of both discovery and translational research to develop a brain selective estrogen receptor modulator (SERM). We have termed such molecules NeuroSERMs to denote their preferential selectivity for activating estrogen mechanisms in brain. Our strategy to develop NeuroSERMs is threefold: (1) determine the target of estrogen action in brain, specifically the estrogen receptor in hippocampal and cortical neurons required for the neurotrophic and neuroprotective actions of estrogen; (2) develop NeuroSERM candidate molecules using three in silico discovery and design strategies and (3) determine the neurotrophic and neuroprotective efficacy of candidate molecules using neuronal responses predictive of clinical efficacy. Using an academic translational research model, a team of scientists with expertise in molecular biology, computational chemistry, synthetic chemistry, proteomics, neurobiology and mitochondrial function have been assembled along with state of the art technologies required to develop candidate NeuroSERM molecules.
• Nilsen, J., & Brinton, R. D. (2004). Mitochondria as therapeutic targets of estrogen action in the central nervous system.. Current drug targets. CNS and neurological disorders, 3(4), 297-313. doi:10.2174/1568007043337193
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  Neuron viability and defense against neurodegenerative disease can be achieved by targeting mitochondrial function to reduce oxidative stress, increase mitochondrial defense mechanisms, or promote energetic metabolism and Ca2+ homeostasis. Exposure to estrogen prior to contact with toxic agents can protect neurons against a wide range of degenerative insults. The proactive defense state induced by estrogen is mediated by complex mechanisms ranging from chemical to biochemical to genomic but which converge upon regulation of mitochondria function. Estrogen preserves ATP levels via increased/enhanced oxidative phosphorylation and reduced ATPase activity thereby increasing mitochondrial respiration efficiency, resulting in a lower oxidative load. In addition, estrogen increases antiapoptotic proteins, Bcl-2 and Bcl-xL, which prevents activation of the permeability transition pore protecting against estrogen-induced increase in mitochondrial Ca2+ sequestration. These effects are likely to be enhanced by antioxidant effects of estrogen, preventing the initiation of the deleterious "mitochondrial spiral". The extent to which each of these mechanisms contribute to the overall proactive defense state induced by estrogen remains to be determined. However, each aspect of the cascade appears to make a significant if not obligatory impact on the neuroprotective effects of estrogens. Moreover each component of the cascade is required for estrogen regulation of mitochondrial function. Mechanisms of estrogen action and results of the clinical efficacy of estrogen therapy for prevention or treatment of Alzheimer's disease are considered in the context of clinical use of estrogen therapy and the design of brain selective estrogens or NeuroSERMs.
• Nilsen, J., & Brinton, R. D. (2004). P1-355 Estrogen regulates mitochondrial function: mechanisms for protection against degenerative insults. Neurobiology of Aging, 25, S199. doi:10.1016/s0197-4580(04)80667-5
• Nilsen, J., & Brinton, R. D. (2004). P1-426 Divergent impact of progestins in vitro predicts Alzheimer's disease risk in women using hormone therapy. Neurobiology of Aging, 25, S220. doi:10.1016/s0197-4580(04)80738-3
• O'Neill, K., Chen, S. H., & Brinton, R. D. (2004). Impact of the selective estrogen receptor modulator, raloxifene, on neuronal survival and outgrowth following toxic insults associated with aging and Alzheimer's disease. EXPERIMENTAL NEUROLOGY, 185(1), 63-80.
• O'Neill, K., Chen, S. H., & Brinton, R. D. (2004). Impact of the selective estrogen receptor modulator, tamoxifen, on neuronal outgrowth and survival following toxic insults associated with aging and Alzheimer's disease. EXPERIMENTAL NEUROLOGY, 188(2), 268-278.
• Zhao, L. Q., Wu, T. W., & Brinton, R. D. (2004). Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neurons. BRAIN RESEARCH, 1010(1-2), 22-34.
• Zhao, L. X., & Brinton, R. D. (2004). Suppression of proinflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha in astrocytes by a V-1 vasopressin receptor agonist: A cAMP response element-binding protein-dependent mechanism. JOURNAL OF NEUROSCIENCE, 24(9), 2226-2235.
• Brinton, R. D., & Nilsen, J. (2003). Effects of estrogen plus progestin on risk of dementia. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 290(13), 1706-1706.
• Nilsen, J., & Brinton, R. D. (2003). Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 100(18), 10506-10511.
• Nilsen, J., & Brinton, R. D. (2003). Mechanism of estrogen-mediated neuroprotection: Regulation of mitochondrial calcium and Bcl-2 expression. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 100(5), 2842-2847.
• Yaffe, K., Volpe, A., Sykova, E., Swaab, D. F., Sturdee, D., Studd, J., Solaini, G., Siseles, N., Simpson, E. R., Simoncini, T., Silva, I. D., Serra, G. B., Schneider, H. P., Schmidt, P., Scarselli, G., Sanna, E., Riecher-roessler, A., Pines, A., Petraglia, F., , Palacios, S., et al. (2003). Hormone replacement therapy in climacteric and aging brain.. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 17(5), 363-78. doi:10.1080/09513590312331290258
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  (2003). Hormone replacement therapy in climacteric and aging brain. Climacteric: Vol. 6, No. 3, pp. 188-203.
• Zhao, L. X., & Brinton, R. D. (2003). Vasopressin-induced cytoplasmic and nuclear calcium signaling in embryonic cortical astrocytes: Dynamics of calcium and calcium-dependent kinase translocation. JOURNAL OF NEUROSCIENCE, 23(10), 4228-4239.
• Zhao, L. X., Chen, S. H., & Brinton, R. D. (2003). An estrogen replacement therapy containing nine synthetic plant-based conjugated estrogens promotes neuronal survival. EXPERIMENTAL BIOLOGY AND MEDICINE, 228(7), 823-835.
• Brinton, R. D. (2002). Selective Estrogen receptor modulators (SERM) for the brain: Recent advances and remaining challenges for developing a NeuroSERM. Drug Development Research, 56(3), 380-392. doi:10.1002/ddr.10090
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  Estrogen regulation of cognitive function and prevention of neurodegenerative disease has come to be of major scientific and clinical importance. While these functions rank paramount among concerns of women during menopause, the neoplastic risks associated with estrogen and hormone replacement therapy lead most women to elect against hormone intervention during menopause or to seek alternative estrogens in an attempt to ameliorate menopause-associated deficits and disease risks. Development of an effective selective estrogen receptor modulator (SERM) for use as an alternative to hormone replacement therapy must address the issues of efficacy in and availability to the brain. Abrief review of estrogen effects on cognition, neuroprotective capability, and disease prevention is provided followed by an analysis of current knowledge regarding SERM efficacy in brain. Lastly, the challenges that remain for developing an effective NeuroSERM™ are considered. Drug Dev. Res. 56:380–392, 2002. © 2002 Wiley-Liss, Inc.
• Brownson, E. A., Brinton, R. D., & Chambers, K. C. (2002). Vasopressin content in select brain regions during extinction of a conditioned taste aversion. Brain research bulletin, 59(2), 125-34.
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  Previous studies have shown that low levels of vasopressin during extinction of conditioned taste avoidance are associated with a faster extinction, that fluid deprivation differentially alters vasopressin levels in various neural areas, and that extinction of conditioned taste avoidance is accelerated in fluid deprived male rats. The following study was designed to identify areas of the brain in which vasopressin levels are different in fluid deprived and nondeprived males during extinction of conditioned taste avoidance. Arginine vasopressin content was determined by radioimmunoassay in the paraventricular nucleus (PVN), medial amygdala (AMe), bed nucleus of the stria terminalis (BNST), nucleus tractus solitarius (NTS), medial septum (MS), lateral septum (LS), and insular cortex (IC) of unconditioned nondeprived males and conditioned males that were maintained on a 23-h fluid deprivation schedule or that were nondeprived. Vasopressin content in the PVN of deprived and nondeprived males differed during extinction. Based on comparisons with unconditioned nondeprived males, this difference was due to an elevation in the vasopressin content of the nondeprived but not the deprived males. These results raise the possibility that a vasopressinergic system in the PVN plays a critical role in the differential extinction rate of fluid deprived and nondeprived males, which will need to be verified by manipulating vasopressin levels in this brain site during extinction of a conditioned taste avoidance.
• Nilsen, J., & Brinton, R. D. (2002). Impact of progestins on estradiol potentiation of the glutamate calcium response. NEUROREPORT, 13(6), 825-830.
• Nilsen, J., & Brinton, R. D. (2002). Impact of progestins on estrogen-induced neuroprotection: Synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. ENDOCRINOLOGY, 143(1), 205-212.
• Nilsen, J., Chen, S. H., & Brinton, R. D. (2002). Dual action of estrogen on glutamate-induced calcium signaling: mechanisms requiring interaction between estrogen receptors and src/mitogen activated protein kinase pathway. BRAIN RESEARCH, 930(1-2), 216-234.
• Zhao, L. X., & Brinton, R. D. (2002). Vasopressin-induced cytoplasmic and nuclear calcium signaling in cultured cortical astrocytes. BRAIN RESEARCH, 943(1), 117-131.
• Zhao, L. X., Chen, Q., & Brinton, R. D. (2002). Neuroprotective and neurotrophic efficacy of phytoestrogens in cultured hippocampal neurons. EXPERIMENTAL BIOLOGY AND MEDICINE, 227(7), 509-519.
• Berger, T. W., Baudry, M., Brinton, R. D., Liaw, J. S., Marmarelis, V. Z., Park, A. Y., Sheu, B. J., & Tanguay, A. R. (2001). Brain-implantable biomimetic electronics as the next era in neural prosthetics. PROCEEDINGS OF THE IEEE, 89(7), 993-1012.
• Brinton, R. D. (2001). Cellular and molecular mechanisms of estrogen regulation of memory function and neuroprotection against Alzheimer's disease: recent insights and remaining challenges.. Learning & memory (Cold Spring Harbor, N.Y.), 8(3), 121-33. doi:10.1101/lm.39601
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  This review focuses on recent advances in our knowledge of estrogen action in the brain. The greatest amount of attention was devoted to those studies that impact our understanding of estrogen regulation of memory function and prevention of degenerative diseases associated with memory systems, such as Alzheimer's disease. A review of recent advances in our understanding of estrogen receptors, both nuclear and membrane, is also presented. Finally, these data are considered in regard to their relevancy to the use of estrogen replacement therapy for cognitive health throughout menopause and the development of an estrogen replacement therapy designed for the unique requirements of the brain.
• Son, M. C., & Brinton, R. D. (2001). Regulation and mechanism of L-type calcium channel activation via V1a vasopressin receptor activation in cultured cortical neurons.. Neurobiology of learning and memory, 76(3), 388-402. doi:10.1006/nlme.2001.4020
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  We have sought to elucidate the biochemical mechanisms that underlie the memory enhancing properties of the neural peptide vasopressin. Toward that goal we have investigated vasopressin induction of calcium signaling cascades, long held to be involved in long-term memory function, in neurons derived from the cerebral cortex, a brain region associated with long-term memory. Our previous studies demonstrated that in cultured cortical neurons, V1a vasopressin receptor (V1aR) activation resulted in a sustained rise in intracellular calcium concentration that was dependent on calcium influx (Son & Brinton, 1998). To investigate the mechanism of V1aR-induced calcium influx, we investigated V1aR activation of the calcium channel subtype(s) in cortical neurons cultured from Sprague-Dawley rat embryonic day 18 fetuses. The results of these analyses demonstrated that the L-type calcium channel blocker nifedipine blocked 250 nM V1 vasopressin receptor agonist (V1 agonist)-induced calcium influx. Intracellular calcium imaging analyses using fura-2AM demonstrated that blockade of L-type calcium channels prevented the 250 nM V1 agonist-induced rise in intracellular calcium concentration. These results indicate that the influx of extracellular calcium via L-type calcium channels is an essential step in the initiation of the V1 agonist-induced rise in intracellular calcium concentration. To determine the mechanism of V1aR activation of L-type calcium channels, regulatory components of the phosphatidylinositol signaling pathway were investigated. The results of these analyses demonstrated that V1 agonist-induced calcium influx was blocked by both a phospholipase C inhibitor (U-73122) and a protein kinase C inhibitor (bisindolylmaleimide I). Further analysis of V1aR activation of protein kinase C (PKC) demonstrated that V1 agonist induced PKC activity within 1 min of exposure in cultured cortical neurons. These data indicate that in cultured cortical neurons, V1aR activation regulates the influx of extracellular calcium via L-type calcium channel activation through a protein kinase-C-dependent mechanism. The results of these studies provide biochemical mechanisms by which vasopressin could enhance memory function. Those mechanisms include a complex cascade that is initiated by activation of the phosphatidylinositol pathway, activation of protein kinase C, followed by phosphorylation of L-type calcium channels to initiate the influx of extracellular calcium to activate a cascade of calcium-dependent release of intracellular calcium.
• Brinton, R. D., Chen, S. H., Montoya, M., Hsieh, D., & Minaya, J. (2000). The estrogen replacement therapy of the Women's Health Initiative promotes the cellular mechanisms of memory and neuronal survival in neurons vulnerable to Alzheimer's disease. MATURITAS, 34, S35-S52.
• Brinton, R. D., Chen, S. H., Montoya, M., Hsieh, D., Minaya, J., Kim, J., & Chu, H. P. (2000). The women's health initiative estrogen replacement therapy is neurotrophic and neuroprotective. NEUROBIOLOGY OF AGING, 21(3), 475-496.
• Chen, Q., Patel, R., Sales, A., Oji, G., Kim, J., Monreal, A. W., & Brinton, R. D. (2000). Vasopressin-induced neurotrophism in cultured neurons of the cerebral cortex: Dependency on calcium signaling and protein kinase C activity. NEUROSCIENCE, 101(1), 19-26.
• Chen, Q., Schreiber, S. S., & Brinton, R. D. (2000). Vasopressin and oxytocin receptor mRNA expression during rat telencephalon development.. Neuropeptides, 34(3-4), 173-80. doi:10.1054/npep.2000.0809
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  We investigated the developmental expression of vasopressin and oxytocin receptor and peptide mRNA using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization. Messenger RNAs for both vasopressin receptor subtypes V(1)a and V(2)were present in the telencephalon from embryonic day 12 to day 20. Both V(1)a and V(2)receptor mRNA increased on day 13 and then remained stable from embryonic day 13 to day 20. Messenger RNA for the vasopressin peptide was also detected in the telencephalon from day 12 to day 20, indicating that vasopressin could be synthesized within the rat cerebral cortex during rat embryonic development. Oxytocin receptor mRNA expression was also present in the telencephalon, but expression levels varied considerably from day 12 to day 20. No oxytocin mRNA expression was detected during rat telencephalon development. Temporal patterns of vasopressin receptor and vasopressin peptide mRNA expression along with oxytocin receptor mRNA suggest a temporal role for vasopressin- and oxytocin-mediated actions during rat telencephalon development.
• Thompson, R. H., Brownson, E. A., & Brinton, R. D. (2000). Spatial, cellular and temporal basis of vasopressin potentiation of norepinephrine-induced cAMP formation.. European journal of pharmacology, 405(1-3), 73-88. doi:10.1016/s0014-2999(00)00543-4
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  This study investigated the spatial distribution of vasopressin V(1) and beta(1)-adrenoceptors within hippocampal subfields and lamina in an attempt to localize the site(s) of interaction between these two receptor systems. In addition, the cell types, neuronal and glial, in which the vasopressin-induced neuromodulation occurs, were identified. Lastly, the temporal constraints of the potentiation induced by vasopressin were investigated. Results of these analyses demonstrated multiple sites within the hippocampus where the interaction between vasopressin and norephinephrine could occur. Moreover, vasopressin-induced potentiation of adrenergic stimulated cyclase occurred in both hippocampal neurons and glia whereas it did not occur in undifferentiated neurons. Analysis of the temporal constraints of vasopressin-induced potentiation revealed that pre-activation of the vasopressin V(1) receptor for 1 min yielded greater potentiation than simultaneous exposure to vasopressin and norepinephrine. These data provide insights into the spatial and temporal characteristics for the interaction between the vasopressin receptor and adrenoceptor systems and provide a cellular and biochemical rationale for the behavioral findings of Kovács and De Wied.
• Brinton, R. D. (1999). A women's health issue: Alzheimer's disease and strategies for maintaining cognitive health.. International journal of fertility and women's medicine, 44(4), 174-85.
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  Data indicate that women are two to three times as likely as men to develop Alzheimer's disease, making this neurodegenerative condition a women's health issue. The challenge of an aging population and women's vulnerability to Alzheimer's disease is reviewed. Strategies to prevent Alzheimer's disease in women are discussed. These strategies include cognitive challenge and exercise, estrogen replacement therapy, anti-inflammatory agents, and antioxidants. Each of these strategies has been associated with a decreased risk of Alzheimer's disease and could have a profound impact on the incidence of Alzheimer's disease in the most vulnerable segment of the population, postmenopausal women.
• Davies, D. L., Bolger, M. B., Brinton, R. D., Finn, D. A., & Alkana, R. L. (1999). In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for ethanol. Psychopharmacology, 141(4), 339-50.
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  The present study uses increased atmospheric pressure as an ethanol antagonist to test the hypothesis that allosteric coupling pathways in the GABA(A) receptor complex represent initial sites of action for ethanol. This was accomplished using behavioral and in vitro measures to determine the effects of pressure on ethanol and other GABAergic drugs in C57BL/6 and LS mice. Behaviorally, exposure to 12 times normal atmospheric pressure (ATA) of a helium-oxygen gas mixture (heliox) antagonized loss of righting reflex (LORR) induced by the allosteric modulators ethanol and pentobarbital, but did not antagonize LORR induced by the direct GABA agonist 4,5,6,7-tetrahydroisoxazolo-pyridin-3-ol (THIP). Similarly, exposure to 12 ATA heliox antagonized the anticonvulsant effects verses isoniazid of ethanol, diazepam and pentobarbital. Biochemically, exposure to 12 ATA heliox antagonized potentiation of GABA-activated 36Cl-uptake by ethanol, flunitrazepam and pentobarbital in LS mouse brain preparations, but did not alter GABA-activated 36Cl- uptake per se. In contrast to its antagonist effect versus other allosteric modulators, pressure did not antagonize these behavioral or in vitro effects induced by the neuroactive steroid, 3alpha-hydroxy-5beta-pregnan-20-one (3alpha,5beta-P). These findings add to evidence that pressure directly and selectively antagonizes drug effects mediated through allosteric coupling pathways. The results fit predictions, and thus support the hypothesis that allosteric coupling pathways in GABA(A) receptors represent initial sites of action for ethanol. Collectively, the results suggest that there may be common physicochemical and underlying structural characteristics that define ethanol sensitive regions of receptor proteins and/or their associated membranes that can be identified by pressure within (e.g., GABA(A)) and possibly across (e.g., GABA(A), NMDA, 5HT3) receptors.
• Foy, M. R., Xu, J., Xie, X., Brinton, R. D., Thompson, R. F., & Berger, T. W. (1999). 17 beta-estradiol enhances NMDA receptor-mediated EPSPs and long-term potentiation. JOURNAL OF NEUROPHYSIOLOGY, 81(2), 925-929.
• Brinton, R. D. (1998). Vasopressin in the mammalian brain: the neurobiology of a mnemonic peptide.. Progress in brain research, 119, 177-99. doi:10.1016/s0079-6123(08)61570-8
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  We have sought to understand the mechanisms by which VP can enhance memory function and in the process determine whether VP fulfills the requirements for neurotransmitter status. The latter goal of proving the neurotransmitter status of VP has been achieved through our findings and the results of many of the scientists contributing to this volume. With respect to elucidating the mechanisms by which VP can enhance memory function, results of our work have shown that VP and its receptors are present in brain regions known to be involved in memory function, that release of VP is inhibited by a factor that inhibits memory function, that VP can significantly enhance the morphological complexity and outgrowth of neurons involved in memory function, that second messenger systems held to be involved in learning and memory, cyclic AMP and calcium signaling pathways, are potentiated and activated by VP, that electrophysiological models of memory function are induced by VP, and that when animals remember a learned association VP content in brain increases over time during the active phase of remembering. Collectively, these studies have taught us a great deal about the sites and mechanisms of VP action and have led us to pursue avenues of investigation that we would not have imagined 15 years ago when we began this work. We stand on the threshold of a new era in our research as we begin our studies of the role VP and its receptors play in the cerebral cortex. Thus far, results of these studies are quite exciting and promise to yield fascinating insights into the complexities of VP action in the most highly developed region of the mammalian brain, the cerebral cortex, the site of abstract reasoning, judgment, complex analysis and the repository of those memories that last a life-time.
• Brinton, R. D., & Yamazaki, R. S. (1998). Advances and challenges in the prevention and treatment of Alzheimer's disease. PHARMACEUTICAL RESEARCH, 15(3), 386-398.
• Brinton, R., Chen, S., Zhang, S., Lorient, V., Manaya, J., Kim, J., & Oji, G. (1998). Comparative analysis of conjugated equine estrogens and the serm raloxifene on outgrowth and survival of neurons critical to memory function and adversely affected in alzheimer's disease. International Journal of Fertility and Menopausal Studies, 43(4), 223.
• Son, M. C., & Brinton, R. D. (1998). Vasopressin-induced calcium signaling in cultured cortical neurons. BRAIN RESEARCH, 793(1-2), 244-254.
• Yamazaki, R. S., Schreiber, S. S., O'neill, K., Gonzalez, C. M., & Brinton, R. D. (1998). Vasopressin-induction of the immediate early gene, NGFI-A, in cultured hippocampal glial cells.. Brain research. Molecular brain research, 57(1), 73-85. doi:10.1016/s0169-328x(98)00069-2
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  Our earlier autoradiographic work had documented a wide distribution of vasopressin receptors in the hippocampus [R.E. Brinton, K.W. Gee, J.K. Wamsley, T.P. Davis, H.I. Yamamura, Regional distribution of putative vasopressin receptors in rat brain and pituitary by quantitative autoradiography, in: Proc. Natl. Acad. Sci. USA, 81 (1984) pp. 7248-7252; C. Chen, R.D. Brinton, T.J. Shors, R.F. Thompson, [Arg 8]-Vasopressin-induction of long lasting potentiation of synaptic transmission in the dentate gyrus, Hippocampus 3 (1993) 193-203.] which suggested the possibility that receptors for vasopressin were present in both neurons and glia. In the periphery, vasopressin is a potent mitogen in select proliferative cell types [E. Rozengurt, A. Legg, P. Pettican, Vasopressin stimulation of mouse 3T3 cell growth, Proc. Natl. Acad. Sci. USA, 76 (1979) pp. 1284-1287.] which also suggested a possible association between vasopressin receptor activation and the proliferative capacity of astrocytes. We therefore investigated whether vasopressin would induce the expression of the immediate early response gene, NGFI-A (also known as zif/268, ZENK, egr-1, krox 24), which is associated with initiation of mitogenesis [M. Sheng, M.E. Greenberg, The regulation and function of c-fos and other immediate early genes in the nervous system, Neuron, 4 (1990) pp. 477-485.]. Cultured hippocampal glial cells were exposed to vasopressin or a selective V1 vasopressin receptor agonist and in situ hybridization for NGFI-A mRNA was conducted. Results of these experiments demonstrated that vasopressin induced a highly significant dose-dependent increase in the number of cells expressing NGFI-A. Studies to determine the receptor subtype mediating vasopressin induction of NGFI-A were conducted utilizing the specific V1 agonist, [Phe2, Ile3, Orn8]-vasopressin. The V1 receptor agonist induced a highly significant dose dependent increase in the number of grains per NGFI-A positive cell. Time course analysis demonstrated that V1 agonist induction of NGFI-A occurred within 5 min, was maximally induced at 15 min of exposure and exhibited a gradual decline within 30 min of exposure which continued to decline over the 60 min time course. Glial cell responsivity was selective in that vasopressin and V1 agonist induction of NGFI-A occurred in a subpopulation of glial cells. Within a sea of glial cells, vasopressin and V1 agonist would induce islands of NGFI-A positive cells. Results of combined immunocytochemical labeling for the astrocyte specific marker, GFAP, and in situ hybridization for NGFI-A demonstrated that V1 agonist-induced NGFI-A expression occurred in GFAP positive cells. We observed no evidence for V1 agonist induction of NGFI-A in neurons. Collectively, these data document that vasopressin, acting via V1 vasopressin receptors, induces a highly significant increase in NGFI-A expression in select GFAP positive hippocampal astrocytes. To our knowledge, these data are the first report of a vasopressin mediated response in hippocampal glial cells. The potential functional significance of these findings is discussed.
• Yamazaki, R. S., Son, M., Chen, Q., & Brinton, R. D. (1998). Vasopressin action in the mammalian cerebral cortex.. Advances in experimental medicine and biology, 449, 211-3. doi:10.1007/978-1-4615-4871-3_27
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  One of the hallmark characteristics of the cerebral cortex is its integrative capacity. Information derived from the external environment, from systems that control homeostasis and from internal conscious and unconscious events all converge onto the cerebral cortex for processing and storage1. A critical, as yet unanswered question, concerns the mechanism(s) by which integration of information occurs in the cerebral cortex. To address this question, we have investigated the receptor system for the neural peptide, vasopressin, which has been found to enhance long-term memory function, a cognitive function associated with the cerebral cortex.
• Brinton, R. D., Proffitt, P., Tran, J., & Luu, R. (1997). Equilin, a principal component of the estrogen replacement therapy premarin, increases the growth of cortical neurons via an NMDA receptor-dependent mechanism. EXPERIMENTAL NEUROLOGY, 147(2), 211-220.
• Brinton, R. D., Tran, J., Proffitt, P., & Montoya, M. (1997). 17 beta-estradiol enhances the outgrowth and survival of neocortical neurons in culture. NEUROCHEMICAL RESEARCH, 22(11), 1339-1351.
• Yamazaki, R. S., Chen, Q., Schreiber, S. S., & Brinton, R. D. (1997). Localization of V1a vasopressin receptor mRNA expression in cultured neurons, astroglia, and oligodendroglia of rat cerebral cortex. MOLECULAR BRAIN RESEARCH, 45(1), 138-140.
• Brinton, R. D. (1996). Equilin, a major component of premarin, increases the growth of neurons from the cerebral cortex.. Journal of The Society for Gynecologic Investigation, 3(2), 70A. doi:10.1016/1071-5576(96)82470-1
• Davies, D. L., Bejanian, M., Parker, E. S., Mørland, J., Bolger, M. B., Brinton, R. D., & Alkana, R. L. (1996). Low level hyperbaric antagonism of diazepam's locomotor depressant and anticonvulsant properties in mice. The Journal of pharmacology and experimental therapeutics, 276(2), 667-75.
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  Exposure to 12 atmospheres absolute (12 ATA) helium oxygen gas (heliox) (low level hyperbaric exposure) antagonizes the behavioral effects of ethanol and n-propanol, but not morphine. These and other results indicate that the mechanism of the antagonism is direct (pharmacodynamic) and selective. Our study further investigates the selectivity of low level hyperbaric antagonism by testing its effectiveness against diazepam, a high affinity binding drug that acts via allosteric modulation of GABAA receptors. C57BL/6J mice received injections i.p. of vehicle or diazepam, and were then exposed to 1 ATA air, 1 ATA heliox or 12 ATA heliox. Exposure to 12 ATA heliox antagonized the locomotor depressant effect of 4 and 6 mg/kg, but not 8 mg/kg diazepam. Hyperbaric exposure also antagonized the anticonvulsant effect of 8 and 24 mg/kg, but not 4 mg/kg, diazepam vs. 300 mg/kg isoniazid. Exposure to 12 ATA heliox did not significantly affect blood concentrations of diazepam or its metabolite n-desmethyl diazepam. The pharmacological characteristics of the antagonism (direct, surmountable, rightward shift in diazepam's dose-response curve) closely matched those seen in previous studies for hyperbaric antagonism of ethanol. The results add to the evidence that low level hyperbaric exposure is a direct, mechanistic antagonist that selectively antagonizes drugs that act via perturbation or allosteric modulation of receptor function. Moreover, the results suggest that allosteric coupling pathways, which transduce binding events on ligand-gated ion channels, may represent initial sites of action for ethanol.
• Parker, E. S., Mørland, J., Parker, E. S., Mørland, J., Davies, D. L., Brinton, R. D., Bolger, M. B., Bejanian, M., & Alkana, R. L. (1996). LOW LEVEL HYPERBARIC ANTAGONISM OF DIAZEPAM'S LOCOMOTOR DEPRESSANT AND ANTICONVULSANT PROPERTIES IN MICE. Journal of Pharmacology and Experimental Therapeutics, 276(2), 667-675.
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  Exposure to 12 atmospheres absolute (12 ATA) helium oxygen gas (heliox) (low level hyperbaric exposure) antagonizes the behavioral effects of ethanol and n-propanol, but not morphine. These and other results indicate that the mechanism of the antagonism is direct (pharmacodynamic) and selective. Our study further investigates the selectivity of low level hyperbaric antagonism by testing its effectiveness against diazepam, a high affinity binding drug that acts via allosteric modulation of GABAA receptors. C57BL/6J mice received injections i.p. of vehicle or diazepam, and were then exposed to 1 ATA air, 1 ATA heliox or 12 ATA heliox. Exposure to 12 ATA heliox antagonized the locomotor depressant effect of 4 and 6 mg/kg, but not 8 mg/kg diazepam. Hyperbaric exposure also antagonized the anticonvulsant effect of 8 and 24 mg/kg, but not 4 mg/kg, diazepam vs. 300 mg/kg isoniazid. Exposure to 12 ATA heliox did not significantly affect blood concentrations of diazepam or its metabolite n-desmethyl diazepam. The pharmacological characteristics of the antagonism (direct, surmountable, rightward shift in diazepam's dose-response curve) closely matched those seen in previous studies for hyperbaric antagonism of ethanol. The results add to the evidence that low level hyperbaric exposure is a direct, mechanistic antagonist that selectively antagonizes drugs that act via perturbation or allosteric modulation of receptor function. Moreover, the results suggest that allosteric coupling pathways, which transduce binding events on ligand-gated ion channels, may represent initial sites of action for ethanol.
• BRINTON, R. D., GONZALEZ, T. M., & CHEUNG, W. S. (1994). VASOPRESSIN-INDUCED CALCIUM SIGNALING IN CULTURED HIPPOCAMPAL NEURONS. BRAIN RESEARCH, 661(1-2), 274-282.
• Brinton, R. D. (1994). The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one induces cytoarchitectural regression in cultured fetal hippocampal neurons. The Journal of Neuroscience, 14(5), 2763-2774. doi:10.1523/jneurosci.14-05-02763.1994
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  The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-THP) acts as a potent allosteric modulator and a direct activator of the GABA-chloride channel complex. This neurosteroid has also been found to protect against seizures that arise from blockade of the GABA- chloride channel complex. Because 3 alpha,5 alpha-THP protects against excitotoxin-induced seizure activity and because seizure activity has been found to be associated with aberrant hippocampal nerve cell growth, the rapid effect of the neurosteroid 3 alpha,5 alpha-THP upon nerve cell growth was investigated using videomicroscopy of hippocampal neurons in culture. Within 40 min of exposure 3 alpha,5 alpha-THP induced a significant decrease in the area and length of neurites. A concomitant decrement in the number and length of filopodia decorating neuritic extensions also occurred within the 40 min of 3 alpha,5 alpha- THP exposure. Both rapid and slow retrograde movement of intracellular organelles was observed in 3 alpha,5 alpha-THP-treated neurons. 3 alpha,5 alpha-THP-induced regression of neuritic extensions occurred only in nerve cells that had not yet established contact with other nerve or glial cells in culture. Established structural connections between neurons or glia did not erode during 3 alpha,5 alpha-THP exposure. Neither the inactive stereoisomer 3 beta-hydroxy-5 beta- pregnan-20-one nor progesterone had a significant effect upon any of the morphological parameters assessed. In approximately 25% of the cells in which 3 alpha,5 alpha-THP had induced regression, subsequent exposure to 17 beta-estradiol induced profuse filopodial growth within 60 sec of exposure. In cultures similar in age to those used in the morphological studies, 3 alpha,5 alpha-THP induced a significant increase in 36Cl- uptake within 10 sec. The magnitude of 36Cl- uptake was comparable to that induced by exposure to 100 microM GABA. In older, more mature cultures in which the nerve cells had established structural connections, 3 alpha,5 alpha-THP protected cells from picrotoxin-induced nerve cell death. These results demonstrate that 3 alpha,5 alpha-THP can induce regression of neuronal morphology within a relatively rapid time frame. 3 alpha,5 alpha-THP induction of 36Cl- uptake within 10 sec suggests that activation of neurosteroid-regulated chloride channels is an initial step in the biochemical mechanism underlying the retraction induced by this progesterone metabolite steroid. In select instances, 17 beta-estradiol induced an extremely rapid reversal of the filopodial regression produced by 3 alpha,5 alpha- THP.(ABSTRACT TRUNCATED AT 400 WORDS)
• Gonzalez, T. M., Cheung, W. S., & Brinton, R. D. (1994). Vasopressin-induced calcium signaling in cultured hippocampal neurons.. Brain research, 661(1-2), 274-82. doi:10.1016/0006-8993(94)91194-0
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  We recently demonstrated that the neural peptide vasopressin (AVP) can act as a neurotrophic factor for hippocampal nerve cells in culture. Because the neurotrophic effect of vasopressin is mediated by the V1 receptor, we investigated AVP activation of calcium signaling pathways in cultured hippocampal neurons. Results of this investigation demonstrate that exposure of cultured hippocampal neurons prelabeled with [3H]myo-inositol to vasopressin induced a significant accumulation of [3H]inositol-1-phosphate ([3H]IP1). The selective V1 vasopressin receptor agonist, [Phe2, Orn2]vasotocin, induced a significant accumulation of [3H]IP1 whereas a selective V2 vasopressin receptor agonist, [deamino1, D-Arg8]-vasopressin, did not. Moreover, V1 agonist-induced accumulation of [3H]IP1 was blocked by the selective V1 vasopressin receptor antagonist d(CH2)5[Tyr(Me)2]-vasopressin. V1 agonist-induced accumulation of [3H]IP1 was concentration dependent and exhibited a steep inverted U-shaped curve that included both stimulation and inhibition of [3H]IP1 accumulation. Time course analysis of V1 agonist-induced accumulation of [3H]IP1 revealed significant increase by 20 min which continued to be significantly elevated for 60 min. Investigation of the effect of closely related peptides on [3H]IP1 accumulation indicated that the vasopressin metabolite peptide AVP4-9 and oxytocin significantly increased [3H]IP1 accumulation whereas the vasopressin metabolite peptide AVP4-8 did not. AVP4-9 and oxytocin induced [3H]IP1 accumulation were blocked by the V1 vasopressin receptor antagonist d(CH2)5[Tyr(Me)2]-vasopressin. V1 receptor activation was associated with a pronounced rise in intracellular calcium. Results of calcium fluorometry studies indicated that V1 agonist exposure induced a marked and sustained rise in intracellular calcium that exhibited oscillations.(ABSTRACT TRUNCATED AT 250 WORDS)
• Monreal, A. W., Fernandez, J. G., & Brinton, R. D. (1994). Vasopressin-induced neurotrophism in cultured hippocampal neurons via V1 receptor activation.. Journal of neurobiology, 25(4), 380-94. doi:10.1002/neu.480250404
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  Structural enhancement of nerve cell morphology has been postulated to be an integral step in the cellular process leading to information storage in the nervous system. To investigate this postulate, we determined whether vasopressin (AVP), a neural peptide that can enhance memory function, would enhance the cytoarchitectural features of hippocampal neurons in culture. Results of these studies demonstrated that in the presence of serum, vasopressin (1 microM), induced a significant increase in the number of neurites, in neuritic length, and in neurite diameter following 48 h of exposure. Morphological complexity was also enhanced following vasopressin exposure as indicated by a significant increase in the number of filopodia/branches, in the sum of branch lengths, and in the number of branch bifurcation points. The number of microspikes decorating neuritic branches was also significantly increased following vasopressin exposure. To determine whether the neurotrophic effect of vasopressin was dependent upon factors present in serum, hippocampal nerve cells were cultured in serum-free media and exposed to 100-1000 nM AVP. Results of these studies demonstrated that in the absence of serum, AVP induced significant enhancement of hippocampal nerve cell growth and that the minimally effective concentration was reduced from 1 microM, as required in the presence serum, to 100 nM. In addition, the time required for a significant increase in nerve cell growth to become apparent decreased from 48 to 24 h. These results demonstrate that AVP-induced neurotrophism is not dependent upon unidentified factors in serum. AVP-induced neurotrophism was found to be mediated by V1 receptor activation. Significant enhancement of nerve cell growth occurred following exposure to V1 receptor agonist (100-1000 nM), whereas exposure to V2 receptor agonist (100-1000 nM) did not increase any of the morphological parameters measured. Considered together, these data indicate that vasopressin can exert a significant neurotrophic effect upon hippocampal nerve cells in culture. Moreover, AVP-induced neurotrophism is a direct effect and not dependent upon unidentified factors present in serum. Enhancement of hippocampal nerve cell growth occurred in the presence of a specific V1 receptor agonist and not following exposure to a V2 agonist, suggesting that activation of the phosphatidyl inositol pathway via V1 receptor activation mediates AVP-induced neurotrophism. Results of these studies are discussed with respect to their implications for understanding vasopressin involvement during neural development and induction of cytoarchitectural modifications associated with memory formation.
• Brinton, R. D. (1993). 17beta-Estradiol Induction of Filopodial Growth in Cultured Hippocampal Neurons within Minutes of Exposure.. Molecular and cellular neurosciences, 4(1), 36-46. doi:10.1006/mcne.1993.1005
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  The rapid effect of 17beta-estradiol upon filopodial growth was investigated using videomicroscopy of hippocampal neurons in culture. Within 1-10 min, 17beta-estradiol induced a significant increase in the number of filopodia decorating neuritic extensions. In addition, the length of existing as well as newly formed filopodia increased significantly during the 10-min 17beta-estradiol exposure. Neurite area and neurite length did not change significantly. The inactive epimer, 17alpha-estradiol, had no effect upon any of the morphological parameters assessed. Similarly, neither progesterone or corticosterone showed a significant influence upon any of the parameters of hippocampal nerve cell growth in culture within the same time frame in which 17beta-estradiol effects were observed. Testosterone induced a significant increase in the number of filopodia without a significant increase in the overall length of the filopodia. Results of these studies demonstrate that 17beta-estradiol can induce rapid changes in nerve cell morphology, suggesting that modification of neuronal circuitry can occur within minutes of exposure, a time base that is consistent with 17beta-estradiol influence upon nerve cell excitability.
• Brownson, E. A., & Brinton, R. D. (1993). Vasopressin-induction of cyclic AMP in cultured hippocampal neurons.. Brain research. Developmental brain research, 71(1), 101-5. doi:10.1016/0165-3806(93)90110-v
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  We investigated the influence of AVP on the induction of the second messenger cyclic AMP (cAMP) during early hippocampal neuron development using cultured hippocampal neurons. Results of those studies revealed that in cultured hippocampal neurons AVP-induces the formation of the second messenger cyclic AMP (cAMP). AVP-induction of cAMP is dose dependent and displays an inverted-U shaped function. Maximal AVP-induction of cAMP accumulation occurred following 15 min of exposure. Results of peptide specificity studies indicated that the vasopressin receptor expressed in cultured hippocampal neurons is pharmacologically promiscuous in that vasopressin metabolite peptides, oxytocin, a V2 receptor agonist and antagonist can all induce the formation of cAMP. In marked contrast, [Phe2,Ile3,Orn8]-vasopressin, a V1 receptor agonist, did not induce cAMP formation. The expression of the cAMP-linked AVP receptor is transient with maximal functional expression occurring between 3 and 4 days in culture which recedes by the fifth day in culture. Because the peptide specificity of the cAMP-linked neural AVP receptor is unique, relative to all other AVP receptors studied thus far, we suggest the term V2b receptor to indicate the distinction of a third (3) type of AVP receptor which is expressed during development (D) of hippocampal nerve cells.
• CHEN, C., BRINTON, R. D., SHORS, T. J., & THOMPSON, R. F. (1993). VASOPRESSIN INDUCTION OF LONG-LASTING POTENTIATION OF SYNAPTIC TRANSMISSION IN THE DENTATE GYRUS. HIPPOCAMPUS, 3(2), 193-204.
• Thompson, R. F., Thompson, R. F., Shors, T. J., Shors, T. J., Chen, C., Chen, C., Brinton, R. D., & Brinton, R. D. (1993). Vasopressin induction of long-lasting potentiation of synaptic transmission in the dentate gyrus.. Hippocampus, 3(2), 193-203. doi:10.1002/hipo.450030211
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  Vasopressin receptors are present in both the developing and mature dentate gyrus of the rat brain and are of the V1 vasopressor type. Because vasopressin has been shown to influence memory function when injected into the dentate gyrus, the influence of this peptide on an electrophysiological model of learning and memory using the field excitatory postsynaptic potential (EPSP) of the dentate gyrus was investigated. Results of these studies showed that nanomolar concentrations of [Arg8]-vasopressin induced a prolonged increase in the amplitude and slope of the evoked population response in the presence of 1.5 mM calcium. Moreover, the expression of the vasopressin-induced potentiation of the EPSP persisted following removal of vasopressin from the perfusion medium. The vasopressin-induced sustained increase has been termed long-term vasopressin potentiation (LTVP). The closely related neuropeptide oxytocin had no effect upon the EPSP of the dentate gyrus. Preincubation of hippocampal slices in a selective V1 antagonist blocked the expression of LTVP. The ability of the V1 antagonist to block LTVP demonstrates that the potentiation induced by vasopressin is receptor-specific. In the presence of 2.5 mM calcium, the effect of vasopressin was opposite to that observed in 1.5 mM calcium. Under the conditions of 2.5 calcium, vasopressin induced a prolonged depression in the amplitude and slope of the EPSP. Expression of both potentiation and depression appeared within 5 minutes of application and persisted for the length of the observation, 60 minutes. These experiments demonstrate that vasopressin can induce long-lasting changes in the excitability of dentate gyrus neurons that are both calcium-dependent and receptor-specific.
• Lehman, C. D., Rodin, J., Mcewen, B. S., & Brinton, R. D. (1991). Impact of environmental stress on the expression of insulin-dependent diabetes mellitus.. Behavioral neuroscience, 105(2), 241-5. doi:10.1037//0735-7044.105.2.241
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  To investigate the influence of environmental factors on inherited tendencies, the impact of chronic environmental stress on the expression of a genetically determined autoimmune disease was explored in the bio-breeding (BB) rat, which is an animal model for human autoimmune insulin-dependent diabetes mellitus. Animals assigned at random to the experimental group received a triad of stressors designed to model chronic moderate stress over a 14-week period. Animals from 25 to 130 days of age were weighed and tested for glycosuria twice weekly. Weekly blood sampling was performed on all animals. Diabetes was diagnosed on the basis of weight loss, 2+ glycosuria, and blood glucose levels of 250+ mg/dl. We found that in the BB rat chronic stress significantly increased the incidence of the phenotypic expression of the gene for Type I diabetes. Eighty percent of the male stress and 70% of the female stress animals developed diabetes, compared with 50% in both control groups. Stressed males developed manifest diabetes at the same time as their matched controls, whereas stressed females had significantly delayed onset in relation to controls.
• O'callaghan, J. P., Brinton, R. E., & Mcewen, B. S. (1991). Glucocorticoids regulate the synthesis of glial fibrillary acidic protein in intact and adrenalectomized rats but do not affect its expression following brain injury.. Journal of neurochemistry, 57(3), 860-9. doi:10.1111/j.1471-4159.1991.tb08230.x
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  Short (5 days)- to long-term (4 months) corticosterone (CORT) administration by injection, pellet implantation, or in the drinking water decreased glial fibrillary acidic protein (GFAP) by 20-40% in hippocampus and cortex of intact rats. In contrast to CORT, adrenalectomy (ADX) caused elevations (50-125%) in hippocampus and cortex GFAP within 12 days of surgery that persisted for at least 4 months. CORT replacement of ADX rats decreased GFAP amount in hippocampus and cortex. The effects of long-term CORT and ADX on GFAP in hippocampus and cortex were also seen in striatum, midbrain, and cerebellum, findings suggestive of brain-wide adrenal steroid regulation of this astrocyte protein. The changes in GFAP amount due to CORT and ADX were paralleled by changes in GFAP mRNA, indicating a possible transcriptional or at least genomic effect of adrenal steroids. Glucocorticoid regulation of GFAP was relatively specific; it could not be generalized to other astrocyte proteins or other major structural proteins of neurons. The negative regulation of GFAP and GFAP mRNA by adrenal steroids suggested that increases in GFAP that result from brain injury may be attenuated by glucocorticoids. However, chronic CORT treatment of intact rats did not reverse or reduce the large increases in GFAP caused by trauma- or toxicant-induced brain damage. Thus, glucocorticoids and injury appear to regulate the expression of GFAP through different mechanisms. In contrast to the lack of effects of CORT on brain damage-induced increases in GFAP, CORT treatment begun in 2-week ADX rats, after an increase in GFAP had time to occur, did reverse the ADX-induced increase in GFAP. These results suggest that the increase in GFAP resulting from ADX is not mediated through an injury-linked mechanism.
• Brinton, R. (1990). Neuromodulation: Associative and nonlinear adaptation. Brain Research Bulletin, 24(5), 651-658. doi:10.1016/0361-9230(90)90003-I
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  Neuromodulation, the interaction between at least two chemical messengers in the nervous system, serves as a mechanism by which biochemical association can occur. A simple, yet compelling, hypothesis is that the criteria for expression of associative learning and memory are subserved by biochemical events which are also associative in nature. A neuromodulatory interaction that has been linked to memory function and which has been the subject of biochemical inquiry is the interaction between the catecholamine, norepinephrine (NE) and the neuropeptide, vasopressin (AVP). Studies described in this report show that vasopressin acts to potentiate norepinephrine (NE)-induced cyclic adenosine monophosphate (cAMP) accumulation in the hippocampus by a calcium-dependent mechanism (13). Results of these studies are considered in the context of the nonlinear properties of synergism and conditionality and in the context of the associative learning requirements of spatial and temporal coupling. Secondly, the calcium dependency of AVP-induced neuromodulation is considered in relation to the calcium dependency for induction of associative long-term potentiation. Lastly, the potential for changes in neuronal morphology in response to neuromodulatory events is considered. By using vasopressin potentiation of noradrenalin-induced cAMP formation as a model system, I have applied the theoretical framework of associative learning and memory to test the hypothesis that neuromodulation can serve as a biochemical analog of associative cognitive events. © 1990.
• Brinton, R. E., & Mcewen, B. S. (1989). Vasopressin neuromodulation in the hippocampus.. The Journal of neuroscience : the official journal of the Society for Neuroscience, 9(3), 752-9. doi:https://doi.org/10.1523/jneurosci.09-03-00752.1989
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  This study explored an effector mechanism associated with the arginine vasopressin (AVP) recognition site in the hippocampus, namely, potentiation of norepinephrine (NE)-induced cAMP accumulation in the surviving hippocampal slice. The biochemical mechanisms that underlie the AVP potentiation were investigated as follows: First, the actions of AVP upon NE-induced accumulation of cAMP in hippocampal slices from rat brain were specific to AVP and not shared by other closely related peptides, namely, oxytocin and AVP4-9. Second, the AVP-induced neuromodulation involved beta-adrenergic receptors, with AVP having no effect on cAMP levels in the absence of NE. Third, the potentiation by AVP was biphasic, with lower AVP concentrations potentiating NE-induced cAMP accumulation, while higher concentrations did not potentiate. Fourth, an antagonist of V1-type AVP receptors blocked AVP potentiation. Fifth, AVP potentiation was dependent upon extracellular calcium concentrations. Sixth, AVP potentiation was blocked by 50 microM trifluoperazine, which is consistent with a calcium-calmodulin involvement but which might also implicate protein kinase C. These alternatives and the nature of the calcium involvement are discussed. AVP actions thus appear to involve interactions between several second-messenger systems and suggest a biochemical mechanism by which AVP exerts its centrally mediated behavioral effects.
• O'callaghan, J. P., Brinton, R. E., & Mcewen, B. S. (1989). Glucocorticoids regulate the concentration of glial fibrillary acidic protein throughout the brain.. Brain Research, 494(1), 159-61. doi:10.1016/0006-8993(89)90156-x
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  The role of glucocorticoids in the in vivo regulation of glial fibrillary acidic protein (GFAP) was examined. Corticosterone administration to adult rats resulted in decreased levels of GFAP throughout the brain whereas adrenalectomy caused levels of GFAP to increase. Corticosterone administration to adrenalectomized rats lowered GFAP levels to values below those of sham controls. Thus, the expression of GFAP throughout the brain appears to be physiologically regulated by adrenal glucocorticoids.
• Brinton, R., & McEwen, B. (1988). Regional distinctions in the regulation of type I and type II adrenal steroid receptors in the central nervous system. Neuroscience Research Communications, 2(1), 37-45.
• Gee, K. W., Bolger, M. B., Brinton, R. E., Coirini, H., & Mcewen, B. S. (1988). Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action.. The Journal of Pharmacology and Experimental Therapeutics, 246(2), 803-12.
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  Further in vitro studies of steroids active at the gamma-aminobutyric acidA (GABAA) receptor regulated Cl- channel labeled by [35S]-t-butylbicyclophosphorothionate ([35S]TBPS) reveal additional structural requirements necessary for activity. Evaluation of selected steroids for activity against TBPS-induced convulsions show similar requirements for activity. Interestingly, steroids (e.g., 5 alpha-pregnan-3 alpha, 20 alpha-diol) were identified that have high potency but limited efficacy as modulators of [35S]TBPS binding. These characteristics are reminiscent of the clinically useful benzodiazepines (BZs) such as clonazepam. However, interactions between the prototypical anesthetic-barbiturate, sodium pentobarbital, and steroids active at the Cl- channel suggest that they do not share a common site of action as allosteric modulators of [35S]TBPS and BZ receptor binding. The most potent steroid evaluated, 5 alpha-pregnan-3 alpha-ol-20-one, modulates [35S]TBPS binding at low concentrations (IC50 approximately 17 nM) in a regionally dependent manner. All [35S]TBPS binding sites appear to be functionally coupled to a steroid "modulatory site." Because several of the active steroids are metabolites of progesterone, their ability to inhibit the binding of [3H]promegestrone to the cytosolic progestin receptor in rat uterus was evaluated. Those steroids showing potent activity at the GABAA receptor-Cl- ionophore were inactive at the intracellular progestin receptor. Such specificity coupled with their high potency provide additional support for the hypothesis that some of these steroids may be involved in the homeostatic regulation of brain excitability via the GABAA-BZ receptor complex.
• Brinton, R. E., Brinton, R. E., & Gruener, R. (1987). Vasopressin promotes neurite growth in cultured embryonic neurons.. Synapse (New York, N.Y.), 1(4), 329-34. doi:10.1002/syn.890010406
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  Vasopressin (AVP) has been identified as a neural peptide which may influence memory function. Because of this action, we investigated the effect of AVP on neurons growing in culture. Vasopressin was found to markedly increase neurite outgrowth from cultured embryonic neurons and to also accelerate the rate of neuritic growth. Maximal stimulation of neurite production occurred after 24-hour incubation in the presence of 1 microM AVP. In AVP-treated cultures the profuse neuritic arborization was characterized by numerous microspikes along the neuritic shafts and at the perimeters of growth cones. These data provide strong evidence for a neurotrophic effect of AVP which, we suggest, may be relevant to neuronal development as well as to morphological changes which occur in the mature nervous system, possibly during memory formation.
• Gee, K., Chang, W., Brinton, R., & McEwen, B. (1987). GABA-dependent modulation of the Cl- ionophore by steroids in rat brain. European Journal of Pharmacology, 136(3), 419-423. doi:10.1016/0014-2999(87)90317-7
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  Steroids inhibit the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to the GABAA-benzodiazepine receptor (GBR) linked Cl- ionophore in a GABA dependent manner but not through the GABAA receptor. The most potent steroid evaluated is a naturally occuring metabolite of progesterone, 3 α-hydroxy,5 α-dihydroprogesterone with an IC50 of ≈ 17 nM. Structural requirements necessary for inhibitory activity coincide with those reported for anticonvulsant and anesthetic actions. Coupled with earlier evidence that these steroids do not act directly at the benzodiazepine receptor nor the [35S]TBPS labeled site to modulate the Cl- ionophore, the possibility is proposed that a distinct membrane-bound 'steroid site' coupled to the GBR-Cl- ionophore complex exists. © 1987.
• Macisaac, L., Spencer, R. L., Mcewen, B. S., Harrelson, A. L., Chao, H. M., & Brinton, R. D. (1987). Corticosteroid receptors in brain: relationship of receptors to effects in stress and aging.. Annals of the New York Academy of Sciences, 512(1), 394-401. doi:10.1111/j.1749-6632.1987.tb24975.x
• McEwen, B., & Brinton, R. (1987). Neuroendocrine aspects of adaptation. Progress in Brain Research, 72(C), 11-26. doi:10.1016/S0079-6123(08)60192-2
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  This chapter discusses the interplay among glucocorticoids and the important neuromodulatory peptide, vasopressin, and the involvement of these neuroactive substances in the process of adaptation. Neural plasticity is characterized by adaptation of neurochemical, neuroanatomical, and behavior systems. Adaptations to environmental stimuli are alterations in the responses of individual and complex ensembles of neurons, which lead to long lasting changes in their functional capabilities. The endocrine system plays an important role in this type of adaptation by acting as a signaling network that triggers both chemical and morphological changes in select populations of neurons and glial cells. The hippocampus responds to glucocorticoids both during the diurnal cycle and in response to stress. Among other effects, results of glucocorticoid actions during the diurnal cycle modify synaptic efficacy within a hippocampal system that is involved in learning and memory and is also influenced by the neuropeptide, vasopressin. A common site of vasopressin and glucocorticoid action is the noradrenaline-stimulation of cyclic AMP formation. © 1987, Elsevier Science Publishers B.V.
• Rostene, W., Mcewen, B. S., Harrelson, A. L., & Brinton, R. D. (1987). Modulatory interactions between steroid hormones, neurotransmitters and neuropeptides in hippocampus.. Advances in biochemical psychopharmacology, 43, 87-102.
• Brinton, R. E., Gehlert, D. R., Wamsley, J. K., Wan, Y. P., & Yamamura, H. I. (1986). Vasopressin metabolite, AVP4-9, binding sites in brain: distribution distinct from that of parent peptide.. Life sciences, 38(5), 443-52. doi:10.1016/0024-3205(86)90069-x
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  Binding sites for the vasopressin metabolite peptide, (AVP4-9), were detected in the rat brain. These binding sites were present in the hilus of the hippocampal formation, superior and inferior colliculus, pontine reticular nuclei, brainstem nuclei, lateral mammillary nucleus, choroid plexus and subfornical organ. The distribution of AVP4-9 binding sites was distinct from that of the parent peptide (1-3). This distinction was apparent in both the regional and intra-regional distribution.
• Brinton, R. E., Gruener, R., Deshmukh, P., & Yamamura, H. I. (1986). In vitro inhibition of vasopressin release in brain by behaviorally relevant ethanol concentrations.. Neuroscience letters, 67(2), 213-7. doi:10.1016/0304-3940(86)90400-3
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  We have investigated the effect of ethanol upon vasopressin (AVP) content in brain and upon in-vitro release of AVP from the rat median eminence. In-vitro ethanol concentrations (5-25 mM), comparable to behaviorally relevant blood ethanol levels, induce a substantial inhibition of AVP release from the median eminence, whereas higher ethanol concentrations (greater than 50 mM) potentiate release. In vivo, ethanol, at a behaviorally relevant blood ethanol concentration (126 mg%), does not produce a significant difference in AVP content in brain although there is a consistent trend towards an increase in the hypothalamus and neurohypophysis. The results are considered in relation to the effects of ethanol on biogenic amine release and to memory impairments induced by low doses of acute ethanol exposure.
• Brinton, R. E., Wamsley, J. K., Yamamura, H. I., Wan, Y. P., & Gehlert, D. R. (1985). Vasopressin metabolite peptide (AVP-(4-9)) binding sites in rat kidney: distribution distinct from vasopressin binding sites.. European journal of pharmacology, 108(3), 321-2. doi:10.1016/0014-2999(85)90457-1
• Brinton, R. E., Wamsley, J. K., Gee, K. W., Yamamura, H. I., & Wan, Y. P. (1984). [3H]oxytocin binding sites in the rat brain demonstrated by quantitative light microscopic autoradiography.. European journal of pharmacology, 102(2), 365-7. doi:10.1016/0014-2999(84)90270-x
• Brinton, R. E., Yamamura, H. I., Wamsley, J. K., Gee, K. W., & Davis, T. P. (1984). Regional distribution of putative vasopressin receptors in rat brain and pituitary by quantitative autoradiography.. Proceedings of the National Academy of Sciences of the United States of America, 81(22), 7248-52. doi:10.1073/pnas.81.22.7248
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  Quantitative light microscopic autoradiography was used to map and characterize the distribution of [3H]arginine vasopressin [( 3H]AVP) binding sites in the rat brain. HPLC analysis for possible degradation of AVP during binding indicated that addition of specific peptidase inhibitors prevented metabolism of AVP. Binding sites for [3H]AVP were observed in the hypothalamus and pituitary as well as in brain regions where AVP may act as a neuroregulator. Within the hypothalamus, dense AVP binding sites were seen in the suprachiasmatic, supraoptic, and paraventricular nuclei. High specific binding was also apparent in the median eminence tubero-infundibular region and in the posterior lobe of the pituitary. [3H]AVP labeling at possible neuroregulatory sites was observed in the hippocampus, lateral septum, superficial cortex, cerebellum, nucleus tractus solitarious, adenohypophysis, and spinal cord.
• Brinton, R. E., Yamamura, H. I., Wamsley, J. K., Hadley, M. E., Gee, K. W., & Davis, T. P. (1983). Light microscopic autoradiographic visualization of [3H]-arginine vasopressin binding sites in rat brain.. Life sciences, 32(16), 1919-24. doi:10.1016/0024-3205(83)90072-3
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  Specific [3H]-arginine vasopressin ([3H]-AVP) binding sites were identified in the rat brain by light microscopic autoradiography. Discrete intrahypothalamic nuclei were densely labelled by [3H]-AVP. High specific binding was observed in the paraventricular and supraoptic nuclei. These binding sites may represent specific receptors for AVP, postulated to exist in the mammalian central nervous system.
• Brinton, R. E., Buck, S. H., Pp, D., Hsiao, S., & Yamamura, H. I. (1982). Radioimmunoassay of vasopressin: development and application to the measurement of intra- and extra-hypothalamic vasopressin levels in the rat.. Western Pharmacology Society, 25(73), 73-4.

Proceedings Publications

• Brinton, R. D., Dagliati, A., Geifman, N., & Peek, N. (2021, May).

  Sex and APOE Genotype Differences Related to Statin Use in The Aging Population

  . In NA, 7, e12156.

Others

• Brinton, R. (2016, September). Neuroendocrinology: Oestrogen therapy affects brain structure but not function. Bat Rev Neurol.