Targeting NMDA Receptors and Brain Estradiol to Rescue Memory in Aging Females

靶向 NMDA 受体和脑雌二醇来挽救老年女性的记忆

• 批准号: 10726257
• 负责人: Hippokratis Kiaris
• 金额: $ 29.8万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726257
• 关键词: Acceleration; Affect; Age; Age-Related Memory Disorders; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Animal Model; Area; Behavior; Brain; Brain Diseases; Centers of Research Excellence; Central Nervous System; Cognition; Cognitive; Cognitive aging; Complement; Data; Deceleration; Dementia; Development; Disease; Disparity; Elderly; Estradiol; Estradiol Receptors; Estrogen deficiency; Estrogens; Exposure to; Failure; Female; Functional disorder; Goals; Health; Hippocampus; Hormone replacement therapy; Hormones; Individual; Intervention; Knowledge; Learning; Longevity; Measures; Memory; Memory Loss; Memory impairment; Menopause; Mission; N-Methyl-D-Aspartate Receptors; National Institute on Aging; Nerve Degeneration; Neurobiology; Neurons; Operative Surgical Procedures; Outcome; Ovarian hormone; Perimenopause; Pharmaceutical Preparations; Population; Postmenopause; Predisposition; Premenopause; Prevalence; Process; Prodrugs; Public Health; Publishing; Rattus; Receptor Signaling; Rejuvenation; Reporting; Research; Research Project Grants; Risk; Role; Severities; Sex Differences; Signal Transduction; South Carolina; Synapses; Testing; Therapeutic; Translations; United States National Institutes of Health; Universities; Woman; Women' s Health; age related; age related cognitive disorder; aged; aging brain; disorder risk; drug development; drug efficacy; efficacy evaluation; excitotoxicity; experience; hormone deficiency; improved; insight; interest; male; men; middle age; neural; neuromechanism; neuroprotection; neurotransmission; normal aging; novel; novel therapeutics; older women; precision medicine; prevent; protective effect; receptor function; remediation; reproductive; restoration; sex; synaptic function; targeted treatment

PROJECT SUMMARY/ABSTRACT Aging women are disproportionately affected by severe memory loss and Alzheimer's disease (AD). The precise mechanisms that impair memory in older women are not fully understood, but the transition into menopause at middle-age, and the ensuing decrease in circulating estrogens, is a consequential inflection point of the female lifespan. Numerous studies document an association between the loss of ovarian hormones, especially estradiol (E2), at menopause and the loss of their protective effects on neural health and cognition. Under normal circumstances, E2 acts upon NMDA receptors (NMDARs) that are essential for learning and memory. In the context of brain disorders, NMDARs gate excitotoxic signaling that can exacerbate neurodegeneration. Loss of E2 in the brain is plausibly situated to influence shifts in NMDAR contributions to neuronal signaling versus survival in brain aging and moderate the effects of AD therapeutics. Consequently, there is a pressing need to develop targeted therapeutics to precisely restore brain E2 and NMDAR activity that could reverse memory loss and reduce AD risk in older, post-menopausal women. Consistent with this view, our preliminary data reveal that a novel therapeutic that potentiates NMDAR function reverses memory loss in older male rats but not in age- matched female rats. The goal of this project is to determine the mechanisms by which female sex and E2 loss accelerate age-related decline of memory and NMDAR functions and to rejuvenate brain E2 levels and sensitivity to NMDAR-directed drugs to rescue memory in older, hormone-deficient females. This project will use normally aging rats to 1) compare effects of approved and novel NMDAR therapeutics on brain and behavior of aging male and female rats and 2) investigate the effects of whole body and brain-specific replacement of E2 in surgically estrogen-deficient, aging females. These studies of NMDAR-directed compounds in well-controlled animal models of aging and estrogen deficiency will be significant because they can provide the necessary mechanistic insights to guide the translation and development of new, targeted therapeutics to prescribe to peri- and post-menopausal women at risk for age-related memory disorders. More broadly, identifying sex-specific and age-appropriate strategies to decelerate fundamental mechanisms that drive neuronal and cognitive aging will broadly improve health outcomes for older women who comprise the largest fraction of those at-risk for AD. These objectives are within the scientific scope of the University of South Carolina's COBRE on Targeted Therapeutics, contribute a unique and distinct complement to ongoing studies of NMDAR-directed therapeutics, and will accomplish rigorous scientific research on differential rates of cognitive aging and the underlying mechanisms of aging leading to increased risk of Alzheimer's disease in pre- and post-menopausal women, specific areas of interest for the National Institute on Aging related to Women's Health.

项目摘要/摘要 老年妇女不成比例地受到严重记忆丧失和阿尔茨海默病（AD）的影响。的精确 老年妇女记忆力受损的机制尚不完全清楚，但进入更年期的过渡期， 中年，以及随之而来的循环雌激素的减少，是女性的一个转折点。 寿命大量研究表明，卵巢激素尤其是雌二醇的丢失与 (E2)在绝经期，以及它们对神经健康和认知的保护作用的丧失。在正常 在某些情况下，E2作用于对学习和记忆至关重要的NMDA受体（NMDAR）。在 在大脑疾病的背景下，NMDAR门控兴奋性毒性信号，可加剧神经变性。损失 大脑中的E2可能会影响NMDAR对神经元信号传导的贡献， 存活在脑老化和中度AD治疗的影响。因此，迫切需要 开发靶向疗法，精确恢复大脑E2和NMDAR活性，从而逆转记忆丧失 并降低老年绝经后妇女的AD风险。与这一观点相一致，我们的初步数据显示， 一种增强NMDAR功能的新疗法逆转了老年雄性大鼠的记忆丧失，但对老年大鼠没有作用- 匹配的雌性大鼠。这个项目的目标是确定女性性和E2损失的机制， 加速与年龄相关的记忆和NMDAR功能下降，并恢复大脑E2水平和敏感性 以NMDAR为导向的药物来挽救老年女性的记忆力。该项目将正常使用 1）比较批准的和新的NMDAR治疗剂对大脑和衰老行为的影响 2）研究全身和脑特异性E2替代对大鼠的影响， 手术雌激素缺乏的老年女性这些针对NMDAR的化合物的研究在良好控制的条件下进行。 衰老和雌激素缺乏的动物模型将是重要的，因为它们可以提供必要的 机械的见解，以指导翻译和开发新的，有针对性的疗法，以规定， 和绝经后妇女的年龄相关的记忆障碍的风险。更广泛地说，识别性别特异性 以及与年龄相适应的策略，以减缓驱动神经元和认知老化的基本机制 将广泛改善老年妇女的健康结果，老年妇女占AD风险的最大部分。 这些目标都在南卡罗来纳州大学的COBRE目标的科学范围内 治疗学为正在进行的NMDAR导向治疗研究提供了独特且独特的补充， 并将完成对认知老化的差异率和潜在的 衰老机制导致绝经前和绝经后妇女患阿尔茨海默病的风险增加， 国家老龄问题研究所对妇女健康感兴趣的具体领域。