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）是晚期晚期阿尔茨海默氏病（AD）的主要遗传决定因素与普通APOE3等位基因相比，增加了风险和APOE2。我们基于团队的工作将研究一种新型的ApoE级联假设（ACH），该假设将阐明疾病机制和告知未来的AD治疗策略。在这里，项目3旨在阐明是否不同的同工型星形细胞和小胶质细胞APOE暴露了影响其功能，聚集和的不同生化特性在衰老和AD发育过程中，淀粉样β（Aβ）的代谢。除星形胶质细胞外，小胶质细胞秘密富裕的脂化apoE随老化和AD发病机理的背景下。与疾病相关小胶质细胞（DAM）在不同的AD鼠标模型上暴露了一个配置的转录签名是中央集线器基因之一。有趣的是，活化的小胶质细胞已显示出诱导神经毒性（A1状）AD中的反应性星形胶质细胞。但是，对于APOE同工型介导的小胶质细胞是否了解很少星形胶质细胞相互作用会影响脑功能和淀粉样蛋白病理。为了解决这些问题，我们有生成的新型诱导小鼠模型，其中人APOE2，APOE3或APOE4基因特别是在星形胶质细胞或小胶质细胞中表达。在AIM 1中，我们将分析星形胶质细胞或小胶质细胞APOE的影响衰老期间的认知功能，脂质代谢，神经炎症和血管完整性的同工型。目标 2，我们将定义星形细胞或小胶质细胞APOE同工型对脑功能，神经炎症和淀粉样病理学的发展。在AIM 3中，我们将确定APOE同工型在星形胶质细胞中的作用小胶质细胞相互作用及其与肿瘤衰老期间和淀粉样蛋白的关联病理。使用独特的鼠标模型和创新技术（即，体内2-Photon成像和体内微透析），我们将全面研究胶质细胞中的APOE同工型如何促进脑认知和淀粉样病理学。更重要的是，将通过与其他项目/核心：1）我们的鼠标模型中APOE粒子的属性将由项目1分析和核心B； 2）将通过核心D测量APOE量和与AD相关的流体生物标志物； 3）淀粉样蛋白病理和神经炎症将由核心C检查； 4）我们的分子表型诱导的APOE鼠标模型将使用多词方法（即保护性，代谢组学，脂质组学和单细胞RNA测序），结果与人类研究通过核F，G； 5）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效应。 6）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鼠标模型的发现核心E中的模型通过具有协同专业知识和资源的多学科团队，我们将合作地了解与衰老有关的疾病和AD中与APOE相关的疾病机制。