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

基本信息

批准号：
10407945
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
项目类别：
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/10407945
关键词：
Abeta clearance Address Affect Age-Months Age-associated memory impairment Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid Amyloid beta-Protein Apolipoprotein E Astrocytes Biochemical Biochemistry Bioinformatics Biological Markers Biology Biometry Blood Vessels Brain 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 Light Lipids 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 base 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 tau Proteins two-photon

项目摘要

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.

项目摘要（APOE U19：项目 3）载脂蛋白 E (apoE) 是晚发性阿尔茨海默病 (AD) 与 APOE4 的主要遗传决定因素与常见的 APOE3 等位基因相比，APOE2 增加了风险，并且具有保护作用。将研究一种新的 ApoE 级联假说 (ACH)，该假说将揭示疾病机制和在此，项目 3 试图阐明是否存在不同的亚型。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、聚集和淀粉样蛋白-β (Aβ) 在衰老和 AD 发展过程中的代谢除了星形胶质细胞、小胶质细胞之外。随着衰老和 AD 发病机制的发生，分泌丰富的脂化 apoE。小胶质细胞 (DAM) 在具有 APOE 的不同 AD 小鼠模型中表现出保守的转录特征作为中心枢纽基因之一，激活的小胶质细胞已被证明会诱导神经毒性。 AD 中的（A1 样）反应性星形胶质细胞然而，关于 apoE 同种型介导的小胶质细胞是否存在，人们知之甚少。星形胶质细胞相互作用影响大脑功能和淀粉样蛋白病理。为了解决这些问题，我们有。产生了新的诱导小鼠模型，其中人类 APOE2、APOE3 或 APOE4 基因被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 的影响。衰老过程中亚型对认知功能、脂质代谢、神经炎症和血管完整性的影响。 2，我们将定义星形胶质细胞或小胶质细胞 apoE 亚型对大脑功能、神经炎症和在目标 3 中，我们将确定 apoE 亚型在星形胶质细胞中的作用。衰老过程中和淀粉样蛋白背景下小胶质细胞的相互作用及其与脑血管的关联使用独特的小鼠模型和创新技术（即体内 2 光子成像和体内微透析），我们将全面研究胶质细胞中的apoE亚型如何促进大脑认知更重要的是，将通过与淀粉样蛋白病理学的相互作用来采用多学科方法。其他项目/核心： 1) 我们的小鼠模型中的 apoE 粒子的特性将由项目 1 进行分析核心 B；2) ApoE 含量和 AD 相关液体生物标志物将通过核心 D 进行测量；淀粉样蛋白病理学和神经炎症将由核心 C 进行检查；4) 我们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），结果通过 Cores F、G 与人类研究相关；我们的数据可以与项目 2 和 4 的研究进行比较，以进一步阐明细胞类型特异性的影响； 6) 可以使用人类 iPSC 衍生的小胶质细胞/星形胶质细胞进一步验证小鼠模型的发现核心 E 中的模型。通过具有协同专业知识和资源的多学科团队，我们将合作了解衰老相关疾病和 AD 中与 apoE 相关的疾病机制。