Genetic modifiers of APOE-related risk for AD

APOE 相关 AD 风险的基因修饰

• 批准号: 10667481
• 负责人: ALISON M GOATE
• 金额: $ 58.16万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667481
• 关键词: Address; Adult; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Apolipoproteins; Astrocytes; Bioinformatics; Biology; Biometry; Brain; Brain Diseases; Cell physiology; Cholesterol; Cognitive; Collaborations; Communities; Complex; Data; Demyelinations; Disease; Disease susceptibility; Dose; EIF2B2 gene; Elderly; Enhancers; Event; Gene Modified; Generations; Genes; Genetic; Genetic study; Genotype; Goals; Hematopoietic stem cells; Homozygote; Human; In Vitro; Isogenic transplantation; Lipids; Macrophage; Mediating; Microglia; Modeling; Molecular; Mus; Myelogenous; Pharmaceutical Preparations; Phenotype; Population; Population Study; Research; Resources; Risk; Sampling; TREM2 gene; Tissues; Variant; Work; abeta deposition; aged; apolipoprotein E-3; apolipoprotein E-4; brain tissue; cytokine; data management; genome editing; genome wide association study; in vivo; induced pluripotent stem cell; insight; lifetime risk; loss of function; neuropathology; new therapeutic target; normal aging; novel; protective allele; response; risk variant; transcriptomics

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.

项目摘要（APOE U19项目5） 阿尔茨海默氏病（AD）风险基因是载脂蛋白E（APOE）。 apoe4与 剂量依赖性风险增加，而APOE2与剂量依赖的风险降低相关 相对于APOE3/3，发病时（AAO）的延迟年龄。基于人群的研究表明APOE4/4 到85岁的纯合子对AD的寿命风险约为60％，而APOE3/3纯合子的寿命风险约为10％。 尽管对广告敏感性有很大影响，但AAO的差异很大（几十年）即使在 单个APOE基因型。我们假设在人口中，既有风险又有保护等位基因 通过在相同的事件级联作用的基因来修改单个APOE基因型中AAO的基因 修改APOE下游的AD风险和AAO（请参阅总体部分以获取APOE的详细说明 级联假设）。在这个项目中，我们将分析公开可用的数据，以识别这些基因 修改APOE4载体和APOE3/3纯合子中的AD风险。初步分析已经确定了罕见 trem2变体是APOE3/3纯合子中AAO的修饰符和稀有的EIF2B3变体作为AAO的修饰符 在ApoE4载体中。 APOE是一种分泌的载脂蛋白，主要在星形胶质细胞中表达。然而， APOE表达在小胶质细胞和其他巨噬细胞的亚群中高度更新，尤其是在 对组织损伤和衰老大脑中的组织损伤和脂质过载的反应，至少部分是 取决于trem2。这与AD特别相关，因为遗传学研究表明 共同的风险等位基因在髓样/小胶质细胞增强剂中特别富集，这表明 APOE基因型及其在AD风险上的遗传修饰符和AAO的遗传修饰符可能是通过对小胶质细胞的影响而介导的 细胞功能。我们假设APOE基因型及其遗传修饰符通过 小胶质细胞功能的调节，尤其是响应衰老和疾病中脑组织损伤的响应。到 解决这一假设，我们将使用ISEOGENIC HIPSC衍生的小胶质细胞（IMGL）评估 APOE基因型及其遗传修饰符（TREM2 R47H＆EIF2B3 S404A）在小胶质细胞功能上 亚源性HIPSC衍生的造血祖细胞（IHPC）的体外和移植到小鼠中 评估APOE基因型及其遗传修饰符（TREM2 R47H＆EIF2B3 S404A）的影响 AD小鼠大脑中的小胶质细胞功能。该项目将与核心C，E一起执行 和G和地址为整体U19项目的目标2、4和6。项目5将确定AAO的新型修饰符 在不同的APOE风险背景的背景下AD的AD，并确定这些分子后果 在体外和体内小胶质功能的新风险基因。这样做，项目5以及项目2-4， 将提供小胶质细胞中APOE功能的见解，从而确定新的治疗靶标的 广告和生成独特的资源/数据将通过核心A与科学界共享。