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

项目总结(APOE U19：总体) 这个U19项目的首要目标是全面了解黑色素瘤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。ε-4等位基因 APOE基因(APOE4)是影响50%-70%AD患者的最强遗传风险因素，而 与常见的ε3等位基因相比，ε2等位基因具有保护性。载脂蛋白E4也是与年龄相关的一个强烈的风险因素 认知功能衰退和血管性认知功能障碍。为了整合现有知识并解决关键差距， 我们提出了一个统一的载脂蛋白E级联假说，结构差异和相关的生化 三种载脂蛋白E亚型之间的性质启动了它们对细胞内一系列事件的不同影响 而系统水平最终会影响包括AD在内的与衰老相关的致病条件。为此，我们 已经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相关老龄化创造一个纽带 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，解决载脂蛋白E三种亚型的结构和生化特性 对功能结果产生洞察力。项目2、3和4将交互研究载脂蛋白E的亚型 在星形胶质细胞、小胶质细胞或血管壁细胞中的表达影响脂代谢、胶质细胞和血管功能， AD相关的病理，以及使用条件小鼠模型和系统的细胞和分子通路- 基于方法。这些研究将产生特定细胞类型的载脂蛋白E/脂蛋白颗粒，这些颗粒将是 通过体内微透析收集，用于结构和生化研究。项目5将进行基因组学 以及遗传分析，以确定AD发病时载脂蛋白E相关年龄的修饰因素。项目2-5中的研究将是 使用健康衰老研究中的死后脑进行神经病理学研究的交互补充 或AD病理学(核心C)，使用人类和小鼠生物样品的生物标记物研究(核心D)，以及 使用人类IPSC衍生的细胞和器官模型的功能研究(核心E)。这份U19提案是 由用于集中式蛋白质组学、脂质组学和 不同动物和IPSC模型以及人死后脑和体液的代谢组学研究 生物群落。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 支持分析大数据集，包括来自单细胞rna-seq的数据集和生物统计支持，以 确保科学严谨。核心G还将与管理核心(核心A)密切合作，以维持ApoE 被指定为EPAAD的Web门户，其中将与科学人员共享知识、资源和数据 社区。Core A还将组织年度ApoE研讨会，以促进协作和参与ApoE 社区。因此，U19将推动基于团队的努力，以产生基本知识来指导疾病- 修改AD和其他与衰老相关的疾病的治疗方法。

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.