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

项目总结/摘要： 女性患阿尔茨海默病（AD）的患病率高于男性，这被认为是 与绝经期神经保护性雌性激素雌激素（E2）的下降有关。虽然E2 众所周知，它的神经保护，潜在的机制仍然在很大程度上未被探索，特别是当它 绝经期E2水平对AD病理生理的影响。显然，这是因为 E2信号传导的复杂性，其由脑区和细胞类型特异性雌激素受体（ER）介导 与许多信号通路相互作用的亚型，其中脑胆固醇代谢是主要相关的 到AD。另一个原因是围绕雌激素化合物在绝经激素中的应用的争议 治疗（HT）。观察性研究提出了HT使用与AD风险之间的负相关性。 然而，一些研究的局限性提出了重要的问题，这些研究的有效性。解决 为了弥补这一知识差距，需要多学科的努力：基于高质量的大型流行病学研究 关于HT使用、心脏代谢疾病史和其他相关变量（包括AD结局）的数据， 需要结合在与人类AD和绝经相关的模型中获得的实验研究。 我们的初步研究结果表明，雌激素受体β（ERβ）具有显着的神经保护作用， 与人类AD相关的动物模型。在AD病理学上可以看到明显的性别差异， 雌激素受体β在诱导绝经后具有神经保护作用。此外，我们的初步数据支持ERβ作为一种 连接E2信号和脑胆固醇代谢的节点。在这个3目标项目中，我们将详细阐述和扩展 这些数据。我们将明确地确定E2和ERβ在现有的神经保护作用中的作用。 以及人类AD和更年期的新型创新模型。同时，我们将利用高质量的流行病学 超过88000名绝经后妇女的数据集，以研究HT使用与AD结局之间的关系 生活中重要的是，我们将获得关于HT使用的详细数据（包括与以下方面相关的开始时间）： 绝经期）、心血管事件史、基线时心脏代谢疾病的患病率、遗传数据 以及多个潜在混杂因素的数据。我们将把我们的数据与国家患者登记册联系起来， AD和非AD痴呆诊断。这样，我们就能准确地确定 E2和HT对AD和非AD痴呆风险的贡献。通过结合流行病学数据， 实验研究中，我们还将确定HT类型，时间，遗传倾向和贡献的影响 特异性ER亚型和脑胆固醇代谢对AD标志物的影响。我们也有可能 验证我们在死后AD大脑中的数据。总的来说，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 雌激素神经保护作用对AD中观察到的性别差异的贡献，这将有助于更好地 为HT的使用和ERβ作为治疗AD的可能临床靶点的评估提供了有依据的建议。

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.