Perimenopause in APOE4 Brain: Obesity and Alzheimer's Pathobiology

项目概要-项目2 我们的计划项目的目标是发现在大脑中发生的生物转化， 在一些实施方案中，这些表型可导致可预测AD病理学发展风险的表型。我们 重点是晚发性AD的主要遗传危险因素，载脂蛋白E（ApoE 4）的ε4等位基因，以及如何 它对女性的AD风险有预防性影响。特别是，我们将研究几个 AD的重要危险因素：年龄、ApoE 4和女性。在项目2中，我们特别强调如何 ApoE 4与女性、围绝经期和肥胖相互作用，协同驱动AD的发展 病理围绝经期开始与年龄相关的消耗卵巢激素的妇女。围绝经 也与体重和肥胖的增加有关，而肥胖通常会导致肥胖，这是一个既定的风险因素 为AD的发展。值得注意的是，肥胖和肥胖不仅受卵巢激素的调节， 也已知会损害生物能量学和增加炎症。因此，围绝经期会产生一种危险的 中年女性AD危险因素的聚集，我们假设ApoE 4加重了这些危险因素。我们 假设AD、ApoE、肥胖和雌激素之间的中心统一联系是炎症。亲- 炎症途径可作为AD发病机制中的关键驱动力， 基因型和肥胖，并抑制雌激素。为了研究这些关系，我们提出三个 所有核心和项目之间高度协作的具体目标。具体目标1：ApoE基因型 在炎症和阿尔茨海默氏症通路的调节相互作用。我们将比较载脂蛋白E 等位基因对AD和炎症相关基因表达、AD神经病理学、代谢和认知的影响 具体目标2：肥胖和ApoE基因型与女性在炎症调节中的相互作用， 阿尔茨海默氏症的路径。我们将确定ApoE状态如何与肥胖在AD调节中相互作用， 炎症相关通路、AD神经病理学、代谢和认知。具体目标3：激素 针对炎症和与ApoE基因型相关的阿尔茨海默病通路的保护干预， 肥胖和围绝经期。我们将评估雌激素为基础的激素治疗在减弱 在存在和不存在肥胖的情况下，在围绝经期和晚期， 绝经

PROJECT SUMMARY – PROJECT 2 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. Our focus is on the primary genetic risk factor for late-onset AD, the ε4 allele of apolipoprotein E (ApoE4), and how it is disproportionally affects AD risk in women. In particular, we will investigate interactions between several significant risk factors for AD: age, the ApoE4, and female sex. In Project 2, our specific emphasis is how ApoE4 interacts with female sex, perimenopause and adiposity to cooperatively drive development of AD pathology. Perimenopause initiates the age-related depletion of ovarian hormones in women. Perimenopause is also linked with increases in body weight and adiposity that often lead to obesity, an established risk factor 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 creates a dangerous convergence of AD risk factors in middle-aged women that we hypothesize is exacerbated by ApoE4. We hypothesize that the central unifying link between AD, ApoE, obesity and estrogen is inflammation. Pro- inflammatory pathways can function as critical driving forces in AD pathogenesis, are elevated by both ApoE4 genotype and obesity, and are inhibited by estrogen. To investigate these relationships, we propose three specific aims that are highly collaborative across all Cores and Projects. Specific Aim 1: ApoE genotype interactions in the regulation of inflammation and Alzheimer's pathways. We will compare the effects of ApoE alleles on expression of AD- and inflammation-related genes, AD neuropathology, metabolism, and cognition Specific Aim 2: Obesity and ApoE genotype interactions with female sex in the regulation of inflammation and Alzheimer's pathways. We will determine how ApoE status interacts with obesity in the regulation of AD- and inflammation-related pathways, AD neuropathology, metabolism and cognition. Specific Aim 3: Hormone interventions for protection against inflammation and Alzheimer's pathways associated with ApoE genotype, obesity and perimenopause. We will evaluate the efficacy of estrogen-based hormone therapies in attenuating the effects of ApoE4, in the presence and absence of obesity, during both perimenopause and late menopause.