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） 最重要的阿尔茨海默病 (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 与风险剂量依赖性降低相关 相对于 APOE3/3，延迟发病年龄 (AAO)。基于人群的研究表明 APOE4/4 纯合子到 85 岁时患 AD 的终生风险约为 60%，而 APOE3/3 纯合子的终生风险约为 10%。 尽管 AAO 对 AD 易感性有很强的影响，但即使在一个时期内，AAO 也存在巨大的变化（几十年）。 单一 APOE 基因型。我们假设在人群中同时存在风险和保护性等位基因 通过在同一级联事件中起作用来修饰单个 APOE 基因型内的 AAO 的基因 修改 ApoE 下游的 AD 风险和 AAO（有关 ApoE 的详细描述，请参阅总体部分） 级联假设）。在这个项目中，我们将分析公开数据来识别基因 改变 APOE4 携带者和 APOE3/3 纯合子的 AD 风险。初步分析发现罕见 TREM2 变体作为 APOE3/3 纯合子中 AAO 的修饰剂，而罕见的 EIF2B3 变体作为 AAO 的修饰剂 在 APOE4 载体中。 ApoE 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 表达在小胶质细胞和其他巨噬细胞亚群中高度上调，特别是在 对衰老或患病大脑中的组织损伤和脂质超载的反应，其方式至少部分是 依赖于 TREM2。这与 AD 特别相关，因为遗传学研究表明 常见风险等位基因在骨髓/小胶质细胞增强子中特别富集，表明 APOE 基因型及其对 AD 风险和 AAO 的遗传修饰因子可能是通过其对小胶质细胞的影响介导的 细胞功能。我们假设 APOE 基因型及其遗传修饰剂通过以下方式改变 AD 风险/AAO 调节小胶质细胞功能，特别是响应衰老和疾病引起的脑组织损伤。到 为了解决这个假设，我们将使用同基因 hiPSC 衍生的小胶质细胞 (iMGL) 来评估 APOE 基因型及其遗传修饰剂（TREM2 R47H 和 EIF2B3 S404A）对小胶质细胞功能的影响 将同基因 hiPSC 衍生的造血祖细胞 (iHPC) 体外移植到小鼠体内 评估 APOE 基因型及其遗传修饰剂（TREM2 R47H 和 EIF2B3 S404A）对 AD 小鼠大脑中小胶质细胞的功能。该项目将与 Cores C、E 合作执行 G 并解决整个 U19 项目的目标 2、4 和 6。项目 5 将确定 AAO 的新型修饰剂 不同 APOE 风险背景下 AD 的发生，并确定这些的分子后果 体外和体内小胶质细胞功能的新风险基因。在此过程中，项目 5 与项目 2-4 一起， 将深入了解小胶质细胞中的 ApoE 功能，从而确定新的治疗靶点 AD 和生成独特的资源/数据，通过核心 A 与科学界共享。