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

我们计划项目的目标是发现在大脑中发生的生物变形 围绝经期转变可导致AD发病风险的表型预测 病理学。在项目3中，我们特别强调卵巢激素对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耗尽。我们假设 更年期引起神经变化，从而减弱雌激素和雌激素的保护作用 黄体酮拮抗与AD发病相关的通路。更年期也与肥胖有关。 体重和肥胖通常会导致肥胖和代谢综合征，条件是 阿尔茨海默病发生的危险因素。值得注意的是，肥胖和肥胖不仅受到调控 通过卵巢荷尔蒙，但也已知损害生物能量和增加炎症。因此， 围绝经期会导致卵巢激素和肥胖症的不利变化，我们的理论是这样的 通过其对生物能量、炎症、 和AD通路。为了研究这些关系，我们提出了三个非常具体的目标 跨所有核心和项目进行协作。特定目标1：大鼠和小鼠模型的前驱体表型 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 以及使用围绝经期啮齿动物模型的路径。具体目标2：肥胖如何与 围绝经期生物能途径、炎症途径和阿尔茨海默病途径的调节？我们将决定 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。特定的 目的3：围绝经期激素干预：预防阿尔茨海默病途径的时机和有效性。 我们将确定提供雌二醇和黄体酮激素治疗的机会之窗 在围绝经期的啮齿动物模型中，使用大鼠和 3xTg-AD小鼠。 相关性(请参阅说明)： 围绝经期导致卵巢激素耗竭和肥胖，我们的理论认为这两者是协同作用的 通过对生物能量、炎症和阿尔茨海默病特异性的影响来促进阿尔茨海默病的发病 小路。这项提案将定义这些重新关系以及激素干预对它们的影响， 绝经后妇女激素治疗必不可少的基础科学信息。

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.