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

我们的计划项目的目标是发现在大脑中发生的生物转化， 可导致预测AD发展风险的表型的围绝经期转变 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耗竭。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，这些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，肥胖和肥胖不仅受卵巢激素的调节，而且已知会损害生物能量学并增加炎症。因此，围绝经期导致卵巢激素和肥胖的不利变化，我们推测它们通过对生物能量、炎症和AD途径的影响在促进AD发病机制中相互作用。为了研究这些关系，我们提出了三个具体的目标，这些目标在所有核心和项目中都是高度协作的。特定目的1：人围绝经期/绝经期大鼠和小鼠模型中的前驱表现型。我们将使用啮齿动物围绝经期模型来描述生殖老化对AD基因和途径的影响。具体目标2：在生物能量、炎症和阿尔茨海默病通路的调节中，肥胖如何与围绝经期相互作用？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。

The goal of our Program Project is to discover the biological transformations that occur in the brain during the perimenopausal transition that can result in phenotypes predictive of risk for development of AD pathology. In Project 3, our specific emphasis is the neuroprotective actions of ovarian hormones on AD pathogenesis. Menopause is characterized in part by depletion 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, conditions 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 bioenergetics and increase inflammation. Thus, perimenopause results in adverse changes to both ovarian hormones and adiposity, which we theorize interact cooperatively in the promotion on AD pathogenesis via their effects on bioenergetic, 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 regulation of bioenergetic, 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.