PERIMENOPAUSE, OVARIAN HORMONES, AND OBESITY: INTERACTIVE REGULATORS OF ALZHEIMER

我们计划项目的目标是发现大脑中发生的生物转化， 可以导致AD发展风险的表型预测的围绝经期转变 病理在项目3中，我们特别强调了卵巢激素对AD的神经保护作用 发病机制更年期的部分特征是卵巢激素的消耗。我们假设 绝经引起神经变化，减弱雌二醇的既定保护作用， 孕酮对AD发病机制相关的途径。更年期也与增加 在体重和肥胖中，这通常会导致肥胖和代谢综合征， 确定了AD发展的风险因素。值得注意的是，肥胖症和肥胖症不仅受到调控， 卵巢激素，但也被称为损害生物能量和增加炎症。因此，在本发明中， 围绝经期导致卵巢激素和肥胖的不利变化，我们认为 在AD发病机制的促进作用中相互作用，通过它们对生物能量，炎症， 和AD途径。为了研究这些关系，我们提出了三个具体的目标， 在所有核心和项目之间进行协作。具体目标1：大鼠和小鼠模型中的前驱症状表型 人类围绝经期/绝经期。我们将描述生殖老化对AD基因的影响 和途径使用啮齿动物模型围绝经期。具体目标2：肥胖如何与 围绝经期在调节生物能量、炎症和阿尔茨海默病通路中的作用？我们将确定 饮食诱导的肥胖对AD途径的影响以及它们如何与生殖衰老相互作用。具体 目的3：围绝经期激素干预：保护阿尔茨海默病通路的时机和有效性。 我们将确定提供雌二醇和孕酮激素治疗的机会窗口， 在我们的啮齿动物围绝经期模型中， 3xTg-AD小鼠。 相关性（参见说明）： 围绝经期导致卵巢激素耗竭和肥胖，我们认为它们相互作用 通过影响生物能量、炎症和阿尔茨海默特异性 途径。该提案将定义这些相关性以及它们如何受到激素干预的影响， 基础科学信息，这是必不可少的优化激素治疗绝经后妇女。

The goal of our Program Project is to discover the biological transformafions that occur in the brain during the perimenopausal transition that can result in phenotypes predicfive of risk for development of AD pathology. In Project 3, our specific emphasis is the neuroprotective acfions of ovarian hormones on AD pathogenesis. Menopause is characterized in part by deplefion of ovarian hormones. We hypothesize that menopause induces neural changes that attenuate the established protective effects of estradiol and progesterone against pathways associated with AD pathogenesis. Menopause is also linked with increases in body weight and adiposity that often lead to obesity and metabolic syndrome, condifions that are established risk factors for the development of AD. Significantly, adiposity and obesity are not only regulated by ovarian hormones, but also are known to impair bioenergefics and increase infiammafion. Thus, perimenopause results in adverse changes to both ovarian hormones and adiposity, which we theorize interact cooperatively in the promofion on AD pathogenesis via their effects on bioenergefic, inflammatory, and AD pathways. To investigate these relationships, we propose three specific aims that are highly collaborative across all cores and projects. Specific Aim 1: Prodromal phenotypes in rat and mouse models of human perimenopause/menopause. We will characterize the effects of reproductive aging on AD genes and pathways using rodent models of perimenopause. Specific Aim 2: How does obesity interact with perimenopause in the regulafion of bioenergefic, inflammatory, and Alzheimer pathways? We will determine the effects of diet-induced obesity on AD pathways and how they interact with reproductive aging. Specific Aim 3: Perimenopausal hormone intervention: timing and efficacy for protection against Alzheimer pathways. We will define the window of opportunity for delivering estradiol and progesterone hormone therapy that effectively protects against AD pathways in our rodent models of perimenopause using both rats and the 3xTg-AD mice. RELEVANCE (See instructions): Perimenopause results in ovarian hormone depletion and adiposity, which we theorize interact cooperatively to promote Alzheimer's pathogenesis via effects on bioenergetic, infiammatory, and Alzheimer-specific pathways. This proposal will define these relafionships and how they are affected by hormone interventions, basic science informafion that is essenfial for opfimizing hormone therapy in postmenopausal women.