Biology and pathobiology of apoE in aging and Alzheimer's disease

项目概要（载脂蛋白E U19：总体） 这个U19项目的首要目标是全面了解的生物学和病理生物学， 载脂蛋白E（apoE）在衰老和阿尔茨海默病（AD）中的作用，为治疗策略提供信息。ε4等位基因 APOE基因（APOE 4）是AD最强的遗传风险因素，影响50-70%的AD患者， 与常见的ε3等位基因相比，ε2等位基因具有保护性。APOE 4也是年龄相关性高脂血症的一个强风险因素。 认知能力下降和血管性认知障碍。为了整合现有知识并弥补关键差距， 我们提出了一个统一的ApoE级联假说，即结构差异和相关的生化 三种apoE亚型之间的特性启动了它们对细胞内级联事件的差异效应， 和系统水平，最终影响衰老相关的致病性疾病，包括AD。为此，我们 组建了一个多学科团队，以协同多个机构的专业知识和资源。通过 整合五个互动项目和七个强大的核心，我们将为apoE相关衰老建立一个联系 研究，与更广泛的科学界分享知识，专业知识和资源。项目1将 与核心B密切合作，研究三种apoE亚型的结构和生化特性， 为功能性成果提供见解。项目2、3和4将交互式研究apoE亚型 在星形胶质细胞、小胶质细胞或血管壁细胞中表达影响脂质代谢、神经胶质和血管功能， AD相关的病理学，以及使用条件性小鼠模型和系统的细胞和分子途径- 基于方法。这些研究将产生细胞类型特异性apoE/脂蛋白颗粒， 通过体内微透析收集用于结构和生化研究。项目5将进行基因组 和遗传分析，以确定AD发病时APOE相关年龄的修饰剂。项目2-5的研究将 交互式补充神经病理学研究，使用健康老龄化研究的死后大脑 或AD病理学（核心C），使用人和小鼠生物标本的生物标志物研究（核心D），以及 使用人iPSC衍生的细胞和类器官模型的功能研究（核心E）。U19提案是 由全面的多组学核心（核心F）支持，用于集中的蛋白质组学，脂质组学， 对各种动物和iPSC模型以及人类死后大脑和体液的代谢组学研究 生物标本生物信息学、生物统计学和数据管理核心（核心G）将提供关键的 支持分析大型数据集，包括来自单细胞RNA-seq和生物统计学的数据集， 确保科学严谨。核心G还将与行政核心（核心A）密切合作， 指定为EPAAD的门户网站，将与科学家共享知识，资源和数据。 社区核心A还将组织年度ApoE研讨会，以促进合作并吸引ApoE 社区因此，U19将推动以团队为基础的努力，以产生指导疾病的基本知识- 改变AD和其他衰老相关疾病的治疗方法。

PROJECT SUMMARY (APOE U19: OVERALL) The overarching goal of this U19 project is to comprehensively understand the biology and pathobiology of apolipoprotein E (apoE) in aging and Alzheimer’s disease (AD) to inform therapeutic strategies. The ε4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for AD impacting 50-70% of all AD patients, while the ε2 allele is protective compared to the common ε3 allele. APOE4 is also a strong risk factor for age-related cognitive decline and vascular cognitive impairment. To integrate existing knowledge and address critical gaps, we propose a unified ApoE Cascade Hypothesis that the structural differences and related biochemical properties among the three apoE isoforms initiate their differential effects on a cascade of events at the cellular and systems levels ultimately impacting aging-related pathogenic conditions including AD. Towards this, we have assembled a multi-disciplinary team to synergize expertise and resources across multiple institutions. By integrating five interactive Projects and seven robust Cores, we will create a nexus for apoE-related aging research, sharing the knowledge, expertise and resources with the broader scientific community. Project 1 will work closely with Core B to address the structural and biochemical properties of the three apoE isoforms to generate insights for functional outcomes. Projects 2, 3 and 4 will interactively study how apoE isoforms expressed in astrocytes, microglia, or vascular mural cells impact lipid metabolism, glial and vascular functions, AD-related pathologies, and cellular and molecular pathways using conditional mouse models and systems- based approaches. These studies will generate cell type-specific apoE/lipoprotein particles that will be collected through in vivo microdialysis for structural and biochemical studies. Project 5 will carry out genomic and genetic analyses to identify modifiers of APOE-related age at onset of AD. Studies in Projects 2-5 will be interactively supplemented by neuropathological studies using postmortem brains from healthy aging studies or with AD pathologies (Core C), biomarker studies using both human and mouse biospecimens (Core D), and functional studies using human iPSC-derived cellular and organoid models (Core E). This U19 proposal is supported by a comprehensive Multi-Omics Core (Core F) for centralized proteomics, lipidomics, and metabolomics studies on various animal and iPSC models, as well as human postmortem brains and fluid biospecimens. The Bioinformatics, Biostatistics, and Data Management Core (Core G) will provide critical supports for analyzing large datasets including those from single-cell RNA-seq and biostatistics supports to ensure scientific rigor. Core G will also work closely with the Administrative Core (Core A) to maintain an ApoE Web Portal designated as EPAAD where knowledge, resources, and data will be shared with the scientific community. Core A will also organize annual ApoE Symposium to promote collaboration and engage the ApoE Community. As such, this U19 will drive a team-based effort to generate essential knowledge to guide disease- modifying therapies for AD and other aging-related conditions.