Astrocytic and microglial apoE in aging and AD

星形胶质细胞和小胶质细胞 apoE 在衰老和 AD 中的作用

• 批准号: 10667470
• 负责人: Long-Jun Wu
• 金额: $ 55.03万
• 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/10667470
• 关键词: Abeta clearance; Address; Affect; Age Months; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Biochemical; Biochemistry; Bioinformatics; Biological Markers; Biology; Biometry; Blood Vessels; Brain; Breeding; Cells; Cerebrovascular system; Cognition; Collaborations; Communities; Data; Development; Disease; Disease associated microglia; Electron Microscopy; Exhibits; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Determinism; Glial Fibrillary Acidic Protein; Homeostasis; Human; Image; Impairment; Innate Immune Response; Knock-in; Late Onset Alzheimer Disease; Liquid substance; Measures; Mediating; Metabolism; Microdialysis; Microglia; Modeling; Mus; Nerve Degeneration; Neuroglia; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Phase; Plasma; Play; Property; Protein Isoforms; Proteomics; Resources; Risk; Role; Sampling; Senile Plaques; Stains; Structural Models; Structure; Testing; Therapeutic; Work; amyloid pathology; apolipoprotein E-3; apolipoprotein E-4; behavioral phenotyping; cell type; cerebrovascular; cognitive function; data management; improved; in vivo; induced pluripotent stem cell; innovative technologies; interdisciplinary approach; lipid metabolism; lipidomics; metabolomics; molecular phenotype; mouse model; multidisciplinary; multiple omics; neuroinflammation; neuropathology; neurotoxic; novel; particle; response; response to injury; sex; single-cell RNA sequencing; specific biomarkers; synaptic function; synergism; tau Proteins; two-photon

PROJECT SUMMARY (APOE U19: Project 3) Apolipoprotein E (apoE) is a major genetic determinant of late-onset Alzheimer’s disease (AD) with APOE4 increases the risk and APOE2 being protective compared with common APOE3 allele. Our team-based work will investigate a novel ApoE Cascade Hypothesis (ACH) which will shed light on the disease mechanisms and inform future therapeutic strategies for AD. Here, Project 3 seeks to elucidate whether different isoforms of astrocytic and microglial apoE exhibit different biochemical properties that impact its function, aggregation, and the metabolism of amyloid-β (Aβ) during aging and AD development. In addition to astrocytes, microglia secrete abundant lipidated apoE with aging and in the context of AD pathogenesis. The disease-associated microglia (DAM) exhibit a conserved transcriptional signature across different AD mouse models with APOE being one of the central hub genes. Interestingly, activated microglia have been shown to induce neurotoxic (A1-like) reactive astrocytes in AD. However, little is known about whether apoE isoform-mediated microglia- astrocyte interaction affects brain functions and amyloid pathologies. To address these questions, we have generated novel inducible mouse models in which human APOE2, APOE3, or APOE4 gene is specifically expressed in astrocytes or microglia. In Aim 1, we will analyze the effects of astrocytic or microglial apoE isoforms on cognitive function, lipid metabolism, neuroinflammation, and vascular integrity during aging. In Aim 2, we will define the impacts of astrocytic or microglial apoE isoforms on brain function, neuroinflammation, and the development of amyloid pathology. In Aim 3, we will determine the role of apoE isoforms in astrocyte- microglia interaction and their association with cerebrovasculature during aging and in the context of amyloid pathology. Using unique mouse models and innovative technologies (ie., in vivo 2-photon imaging and in vivo microdialysis), we will comprehensively investigate how apoE isoforms in glia cells contribute to brain cognition and amyloid pathology. More importantly, multi-disciplinary approaches will be employed by interacting with other projects/cores: 1) The properties of apoE particles from our mouse models will be analyzed by Project 1 and Core B; 2) ApoE amounts and AD-related fluid biomarkers will be measured through Core D; 3) The amyloid pathologies and neuroninflammation will be examined by Core C; 4) The molecular phenotypes of our inducible apoE mouse models will be examined using multi-omics approaches (ie., proteomics, metabolomics, lipidomics and single cell RNA sequencing), with results correlating with human studies through Cores F, G; 5) Our data can be compared with studies from Projects 2 and 4 to further elucidate the cell type-specific effects; and 6) Findings from mouse models can be further validated using human iPSC-derived microglia/astrocyte models in Core E. Through multidisciplinary team with synergized expertise and resources, we will collaboratively understand the apoE-associated disease mechanisms in aging-related conditions and AD.

项目概要（APOE U19：项目3） 载脂蛋白E（apoE）是晚发性阿尔茨海默病（AD）的主要遗传决定因子，载脂蛋白E 4 与常见的APOE 3等位基因相比，APOE 2具有保护作用。我们的团队工作 将研究一种新的ApoE级联假说（ACH），这将揭示疾病的机制， 为未来的AD治疗策略提供信息。在这里，项目3试图阐明是否不同亚型的 星形胶质细胞和小胶质细胞apoE表现出不同的生化特性，影响其功能、聚集和 β淀粉样蛋白（Aβ）在衰老和AD发生发展过程中的代谢。除了星形胶质细胞， 随着年龄的增长和AD发病机制的背景下分泌大量的脂化apoE。疾病相关 小胶质细胞（DAM）在不同的载脂蛋白E AD小鼠模型中表现出保守的转录特征 作为中心基因之一。有趣的是，激活的小胶质细胞已被证明可以诱导神经毒性 （A1样）反应性星形胶质细胞在AD中。然而，关于apoE亚型介导的小胶质细胞- 星形胶质细胞相互作用影响脑功能和淀粉样病变。为了解决这些问题，我们有 产生了新的诱导型小鼠模型，其中人APOE 2、APOE 3或APOE 4基因特异性地 在星形胶质细胞或小胶质细胞中表达。在目标1中，我们将分析星形胶质细胞或小胶质细胞apoE对 同种型对认知功能、脂质代谢、神经炎症和衰老过程中血管完整性的影响。在Aim中 2，我们将确定星形胶质细胞或小胶质细胞apoE亚型对脑功能，神经炎症， 淀粉样病变的发展。在目标3中，我们将确定apoE亚型在星形胶质细胞中的作用- 在衰老和淀粉样蛋白背景下小胶质细胞的相互作用及其与血管系统的联系 病理使用独特的小鼠模型和创新技术（即，体内双光子成像和体内 微透析），我们将全面研究胶质细胞中的apoE亚型如何有助于脑认知 和淀粉样蛋白病理学。更重要的是，将采用多学科方法， 其他项目/核心：1）来自我们小鼠模型的apoE颗粒的特性将由项目1进行分析 和核心B; 2）ApoE量和AD相关液体生物标志物将通过核心D测量; 3）ApoE量和AD相关液体生物标志物将通过核心D测量。 淀粉样蛋白病理和神经炎症将通过核心C检查; 4）我们的研究的分子表型 将使用多组学方法（即，蛋白质组学，代谢组学， 脂质组学和单细胞RNA测序），结果与通过Cores F、G进行的人类研究相关; 5） 我们的数据可以与项目2和项目4的研究进行比较，以进一步阐明细胞类型特异性效应; 和6）来自小鼠模型的发现可以使用人iPSC衍生的小胶质细胞/星形胶质细胞进一步验证 Core E中的模型。通过多学科团队协同专业知识和资源，我们将 合作了解衰老相关疾病和AD中apoE相关的疾病机制。