Perimenopause in APOE4 Brain: Obesity and Alzheimer's Pathobiology

项目摘要--项目2 我们计划项目的目标是发现在大脑中发生的生物变化 围绝经期转变可导致预测AD病理发展风险的表型。我们的 重点是迟发性AD的主要遗传风险因素，载脂蛋白E的载脂蛋白4等位基因(ε4)，以及如何 它不成比例地影响女性患阿尔茨海默病的风险。特别是，我们将研究几个 AD的重要危险因素：年龄、载脂蛋白E4和女性。在项目2中，我们特别强调如何 载脂蛋白E4与女性性别、围绝经期和肥胖相互作用共同推动AD的发展 病理学。围绝经期会引发女性卵巢激素的年龄相关耗竭。围绝经期 它还与体重增加和肥胖有关，这往往会导致肥胖，这是一个公认的风险因素 对于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，而且 众所周知，它还会损害生物能量学，增加炎症。因此，围绝经期会造成危险的 我们推测载脂蛋白E4加剧了中年女性AD危险因素的趋同。我们 假设AD、ApoE、肥胖和雌激素之间的中心统一联系是炎症。支持- 炎症通路可作为AD发病的关键驱动力，ApoE4和ApoE4均可上调 基因和肥胖症，并被雌激素抑制。为了研究这些关系，我们提出了三个 跨所有核心和项目高度协作的特定目标。具体目标1：载脂蛋白E基因 炎症和阿尔茨海默氏症途径调节中的相互作用。我们将比较ApoE的效果 AD和炎症相关基因表达、AD神经病理、代谢和认知的等位基因 特定目标2：肥胖和载脂蛋白E基因与女性性别的相互作用在调节炎症和 阿尔茨海默氏症路径。我们将确定载脂蛋白E状态如何在AD调节中与肥胖相互作用-和 炎症相关通路，阿尔茨海默病的神经病理，代谢和认知。具体目标3：荷尔蒙 与载脂蛋白E基因相关的预防炎症和阿尔茨海默病途径的干预措施， 肥胖和围绝经期。我们将评估基于雌激素的激素疗法在减重方面的疗效。 有无肥胖对围绝经期和晚期载脂蛋白E4的影响 更年期。

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.