Understanding the role of menopause and estrogen receptor activation for Alzheimer's disease risk

项目摘要/摘要： 女性患阿尔茨海默病(AD)的患病率比男性高，据信这是 与更年期神经保护性女性性激素雌激素(E2)的下降有关。虽然E2是 以其神经保护而闻名，其潜在的机制在很大程度上仍未被探索，特别是当 更年期雌激素水平对AD病理生理的影响。显然，这样做的一个原因是 由脑区和细胞类型特异性雌激素受体(ER)介导的E2信号的复杂性 异构体与多种信号通路相互作用，其中与脑胆固醇代谢密切相关 到公元后。另一个原因是围绕雌激素类化合物在更年期激素中使用的争议。 治疗(HT)。观察性研究提出了使用羟色胺与AD风险之间的负相关关系。 然而，几项研究的局限性对这些研究的有效性提出了重要的问题。致信地址 这一知识差距需要多学科的努力：基于高质量的大规模流行病学研究 关于羟色胺使用情况、心脏代谢病史和其他相关变量(包括AD结果)的数据如下 需要结合在与人类AD和更年期相关的模型中获得的实验研究。 我们的初步结果表明，雌激素受体β(ER-β)具有显著的神经保护作用。 一种与人类AD相关的动物模型。在AD病理上可以看到明显的性别差异，其中 ER-β的神经保护作用发生在诱导绝经后。此外，我们的初步数据支持ERβ作为 连接E2信号和脑胆固醇代谢的节点。在这个三个目标的项目中，我们将详细阐述和扩展 在这些数据上。我们将在Available中明确确定E2和ERβ的神经保护作用 以及创新的人类AD和更年期模型。同时，我们将利用高质量的流行病学 对超过8.8万名绝经后妇女的数据集进行研究，以研究羟色胺使用与AD结局之间的关系 在生活中。重要的是，我们将能够访问有关使用HT的详细数据(包括与以下内容相关的启动时间 更年期)、心血管事件史、基线时心脏代谢性疾病的患病率、遗传数据 以及关于多个潜在混杂因素的数据。我们将把我们的数据与全国患者登记联系起来，以确定 AD以及非AD痴呆症的诊断。通过这种方式，我们将准确地定位全人口 雌二醇和羟色胺对AD和非AD痴呆风险的贡献。通过将流行病学数据与 实验研究我们还将确定高血压的类型、时间、遗传易感性和贡献 AD标志物上特异性ER亚型和脑胆固醇代谢的关系。我们也有可能 在死后的AD大脑中验证我们的数据。总体而言，我们研究团队的综合专业知识使我们能够 比较不同流行病学和实验数据集获得的数据，以准确确定 雌激素神经保护对AD患者性别差异的贡献，这将有助于更好地 对HT的使用和ERβ作为对抗AD的可能临床靶点的评估提出了明智的建议。

PROJECT SUMMARY/ABSTRACT: Women have a higher prevalence of developing Alzheimer’s disease (AD) than men, which is believed to be associated with the drop in neuroprotective female sex hormone estrogen (E2) at menopause. Although E2 is well known for its neuroprotection, the underlying mechanisms are still largely unexplored, especially when it comes to the impact of menopausal E2 levels on the pathophysiology of AD. Clearly, a reason for this is the complexity of E2 signaling, which is mediated by brain area and cell-type specific estrogen receptor (ER) isoforms interacting with many signaling pathways, of which brain cholesterol metabolism is of major relevance to AD. Another reason is the controversies surrounding use of estrogenic compounds in menopausal hormone therapies (HT). Observational studies put forward an inverse association between HT use and risk of AD. However, several study limitations have raised important questions on the validity of these studies. To address this gap in knowledge, multidisciplinary efforts are needed: Large epidemiological studies based on high quality data on HT use, cardiometabolic disease history and other variables of pertinence including AD outcome are needed in combination with experimental studies acquired in models relevant to human AD and menopause. Our preliminary results suggest that the estrogen receptor beta (ERβ) has significant neuroprotective effects in an animal model relevant to human AD. Clear sex differences on AD pathology can be seen and the largest neuroprotective effect of ERβ is after induced menopause. In addition, our preliminary data supports ERβ as a node linking E2 signaling and brain cholesterol metabolism. In this 3-aim project, we will elaborate and expand on these data. We will unambiguously determine the neuroprotective contribution of E2 and ERβ in available and novel innovative models of human AD and menopause. In parallel, we will utilize high quality epidemiological data sets of over 88 000 postmenopausal women to study associations between HT use and AD outcome later in life. Importantly, we will have access to detailed data on HT use (including timing of initiation in relation to menopause), history of cardiovascular events, prevalence of cardiometabolic disease at baseline, genetic data and data on multiple potential confounding factors. We will link our data to national patient registers to identify AD as well as non-AD dementia diagnoses. In this way, we will accurately pinpoint the population-wide contribution of E2 and HT to AD and non-AD dementia risk. By combining the epidemiologic data with experimental studies we will also determine the effect of HT type, timing, genetic predispositions and contribution of specific ER isoforms and brain cholesterol metabolism on markers of AD. We also have the possibility to validate our data in postmortem AD brains. Overall, the combined expertise of our research team allows us to compare data acquired across different epidemiologic and experimental data sets to accurately determine the contribution of estrogenic neuroprotection to the sex differences observed in AD, which will contribute to better informed recommendations for HT use and evaluation of ERβ as a possible clinical target to combat AD.