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

项目摘要/摘要 老年妇女受到严重记忆力丧失和阿尔茨海默病(AD)的影响不成比例。精准的 老年女性记忆受损的机制尚未完全了解，但在更年期过渡到更年期 中年，以及随之而来的循环雌激素的减少，是女性的一个相应的拐点。 寿命。大量研究表明，卵巢激素，尤其是雌二醇的丢失 (E_2)、绝经期和丧失对神经健康和认知的保护作用。低于正常 在这种情况下，E2作用于对学习和记忆至关重要的NMDA受体(NMDAR)。在 在大脑紊乱的背景下，NMDAR信号通路的兴奋性毒性信号可能会加剧神经退化。损失 大脑中的E2似乎位于影响NMDAR对神经元信号转导的贡献的位置，而不是 延缓脑老化和AD治疗的效果。因此，迫切需要 开发靶向疗法，精确恢复大脑E2和NMDAR活动，从而逆转记忆丧失 并降低老年绝经后妇女患AD的风险。与这一观点一致，我们的初步数据显示， 一种增强NMDAR功能的新疗法可以逆转老年雄性大鼠的记忆丧失，但对老年大鼠没有影响。 匹配的雌性大鼠。这个项目的目标是确定女性性别和雌二醇丢失的机制 加速记忆和NMDAR功能的增龄性衰退，恢复大脑E2水平和敏感度 NMDAR指导的药物来挽救荷尔蒙缺乏的老年女性的记忆。该项目将正常使用 1)比较已批准的和新的NMDAR疗法对脑和衰老行为的影响 雄性和雌性大鼠和2)研究全身和脑特异性的E2替代对小鼠的影响。 手术中雌激素缺乏，年迈的女性。NMDAR导向化合物的这些研究在良好控制下 衰老和雌激素缺乏的动物模型将具有重要意义，因为它们可以提供必要的 指导新的、有针对性的疗法的翻译和开发的机械性见解，以开出针对围产期的处方 以及绝经后的女性面临与年龄相关的记忆障碍的风险。更广泛地说，识别特定性别 以及适合年龄的策略，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，这些妇女构成AD风险的最大比例。 这些目标是在南卡罗来纳大学科布雷关于目标的科学范围内 治疗学，对正在进行的NMDAR导向疗法的研究做出了独特和独特的补充， 并将完成对认知衰老的不同速度和潜在原因的严格科学研究 导致绝经前和绝经后妇女阿尔茨海默病风险增加的衰老机制， 与妇女健康有关的国家老龄问题研究所感兴趣的具体领域。

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.