Genetic modifiers of APOE-related risk for AD

项目总结(APOE U19项目5) 最重要的阿尔茨海默病(AD)危险基因是载脂蛋白E(APOE)。ApoE4与 剂量依赖性风险增加，而APOE2与剂量依赖性风险降低和 发病年龄延迟(AAO)，相对于APOE3/3。基于人群的研究表明，APOE4/4 到85岁时，纯合子患阿尔茨海默病的风险约为60%，而APOE3/3纯合子约为10%。 尽管对阿尔茨海默病的易感性有如此强烈的影响，但AAO在一年内也存在巨大的差异(几十年) 单一载脂蛋白E基因。我们假设，在人类群体中，既有危险等位基因，也有保护性等位基因 通过在同一系列事件中起作用来改变单一APOE基因中的AAO的基因 修改APOE下游的AD Risk和AAO(有关ApoE的详细说明，请参阅整节 级联假说)。在这个项目中，我们将分析公开可用的数据来识别 修改APOE4携带者和APOE3/3纯合子的AD风险。初步分析确定了罕见的 在APOE3/3纯合子中作为AAO修饰物的TREM2变异体和作为AAO修饰物的罕见EIF2B3变异体 在APOE4携带者中。载脂蛋白E是一种分泌型载脂蛋白，主要在星形胶质细胞中表达。然而， APOE在小胶质细胞和其他巨噬细胞亚群中高度上调，尤其是在 对老年人或患病大脑中的组织损伤和脂质过载的反应，至少部分地 依赖于TREM2。这与阿尔茨海默病特别相关，因为遗传学研究表明 常见的危险等位基因在髓系/小胶质细胞增强剂中特异性地丰富，这表明 载脂蛋白E基因及其基因修饰物对AD和AAO的影响可能是通过其对小胶质细胞的影响而实现的 细胞功能。我们假设载脂蛋白E基因及其遗传修饰物通过改变AD风险/AAO 小胶质细胞功能的调节，特别是对衰老和疾病中的脑组织损伤的反应。至 为了解决这一假设，我们将使用同基因的HiPSC来源的小胶质细胞(IMGL)来评估 载脂蛋白E基因及其遗传修饰物(TREM2 R47H和EIF2B3 S404A)对小胶质细胞功能的影响 同基因hPSC来源的造血祖细胞体外移植 评估载脂蛋白E基因及其遗传修饰物(TREM2 R47H和EIF2B3 S404A)对 阿尔茨海默病小鼠脑内小胶质细胞功能。该项目将与C、E核合作执行 和G，并涉及整个U19项目的目标2、4和6。项目5将确定AAO的新修饰剂 在不同的APOE风险背景下AD的发生，并确定这些因素的分子后果 体内和体外影响小胶质细胞功能的新危险基因。在这样做时，项目5与项目2-4一起， 将提供对小胶质细胞载脂蛋白E功能的洞察，从而确定新的治疗靶点 广告和生成独特的资源/数据，通过核心A与科学界共享。

PROJECT SUMMARY (APOE U19 Project 5) The most important Alzheimer’s disease (AD) risk gene is apolipoprotein E (APOE). APOE4 is associated with a dose dependent increase in risk, while APOE2 is associated with a dose dependent decrease in risk and delayed age at onset (AAO), relative to APOE3/3. Population-based studies have demonstrated that APOE4/4 homozygotes have ~60% life-time risk for AD by age 85 yrs compared to ~10% in APOE3/3 homozygotes. Despite this strong effect on AD susceptibility, there is huge variation (several decades) in AAO even within a single APOE genotype. We hypothesize that in human populations there are both risk and protective alleles in genes that modify AAO within a single APOE genotype by acting within the same cascade of events that modify AD risk and AAO downstream of APOE (see Overall section for detailed description of the ApoE Cascade Hypothesis). In this project we will analyze publicly available data to identify genes that modify AD risk in APOE4 carriers and APOE3/3 homozygotes. Preliminary analyses have identified rare TREM2 variants as modifiers of AAO in APOE3/3 homozygotes and rare EIF2B3 variants as modifiers of AAO in APOE4 carriers. ApoE is a secreted apolipoprotein that is primarily expressed in astrocytes. However, APOE expression is highly upregulated in subpopulations of microglia and other macrophages, particularly in response to tissue damage and lipid overload in the aged or diseased brain, in a manner that is at least in part dependent on TREM2. This is of particular relevance to AD because genetic studies have demonstrated that common risk alleles are specifically enriched in myeloid/microglial enhancers, suggesting that the effects of APOE genotype and its genetic modifiers on AD risk and AAO may be mediated by their effects on microglial cell function. We hypothesize that APOE genotype and its genetic modifiers alter AD risk/AAO through modulation of microglial cell function, particularly in response to brain tissue damage in aging and disease. To address this hypothesis we will use isogenic hiPSC-derived microglia (iMGL) to assess the impact of APOE genotype and its genetic modifiers (TREM2 R47H & EIF2B3 S404A) on microglial cell function in vitro and transplantation of isogenic hiPSC-derived hematopoietic progenitor cells (iHPCs) into mice to assess the impact of APOE genotype and its genetic modifiers (TREM2 R47H & EIF2B3 S404A) on microglial cell function in AD mouse brains. This project will be performed in collaboration with Cores C, E and G and addresses aims 2, 4 and 6 of the overall U19 project. Project 5 will identify novel modifiers of AAO of AD in the context of different APOE risk backgrounds and determine the molecular consequences of these novel risk genes on microglial function in vitro and in vivo. In so doing, Project 5, together with Projects 2-4, will provide insight into ApoE function in microglia leading to the identification of novel therapeutic targets for AD and generation of unique resources/data to be shared with the scientific community through Core A.