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

apoE 在衰老和阿尔茨海默病中的生物学和病理学

• 批准号: 10667435
• 负责人: ALISON M GOATE
• 金额: $ 652.39万
• 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/10667435
• 关键词: Acceleration; Address; Age; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid beta-Protein; Animals; Apolipoprotein E; Astrocytes; Automobile Driving; Autopsy; Biochemical; Biochemistry; Bioinformatics; Biological Markers; Biological Models; Biology; Biometry; Biophysics; Blood Vessels; Brain; Cell Nucleus; Cells; Collaborations; Collection; Communities; Data; Data Set; Development; Disease; Disease Pathway; Ensure; Event; Fostering; Genes; Genetic; Genomics; Genotype; Goals; Human; Impaired cognition; Institution; Interruption; Knowledge; Link; Lipid Binding; Lipids; Lipoproteins; Liquid substance; Mediating; Microdialysis; Microglia; Modeling; Molecular; Multiomic Data; Mus; Neurosciences; Organoids; Outcome; Pathogenicity; Pathologic; Pathology; Pathway interactions; Physiological; Post-Translational Protein Processing; Prevention strategy; Property; Protein Isoforms; Proteins; Proteomics; Reagent; Recommendation; Research; Research Personnel; Resource Sharing; Resources; Risk; Risk Factors; Structure; System; Testing; Therapeutic; Time; United States National Institutes of Health; Vascular Cognitive Impairment; Work; age related; aging brain; biomarker discovery; biophysical properties; brain cell; cell type; data management; design; functional outcomes; genetic analysis; genetic risk factor; healthy aging; improved; in vivo; induced pluripotent stem cell; innovation; insight; large datasets; lipid metabolism; lipidomics; metabolomics; mouse model; multidisciplinary; multiple omics; neuropathology; particle; prevent; protective allele; risk variant; single-cell RNA sequencing; structural biology; symposium; synergism; targeted treatment; tau Proteins; therapeutic development; treatment strategy; web portal

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.

项目摘要（APOE U19：总体） 这个U19项目的总体目标是全面了解 衰老和阿尔茨海默氏病（AD）中的载脂蛋白E（APOE），以告知治疗策略。 ε4等位基因 APOE基因（APOE4）是影响所有AD患者50-70％的广告的强大遗传危险因素，而 与常见的ε3等位基因相比，ε2等位基因受到保护。 APOE4也是与年龄有关的强大风险因素 认知能力下降和血管认知障碍。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APOE级联假设，即结构差异和相关的生化假设 三种APOE同工型之间的特性对细胞处的级联事件产生了不同的影响 系统水平最终会影响包括AD在内的与衰老相关的致病状况。对此，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协同。经过 整合了五个互动项目和七个健壮的核心，我们将为与APOE相关的衰老创建一个Nexus 研究，与更广泛的科学界共享知识，专业知识和资源。项目1将 与核心B紧密合作，以解决三种APOE同工型的结构和生化特性 生成功能结果的见解。项目2、3和4将交互式研究APOE同工型 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， 使用条件小鼠模型以及系统 - 基于方法。这些研究将产生细胞类型特异性的APOE/脂蛋白颗粒，这将是 通过体内微透析收集结构和生化研究。项目5将执行基因组 和遗传分析以鉴定AD发作时与APOE相关年龄的修饰符。项目2-5的研究将是 使用健康衰老研究的事后大脑进行神经病理学研究的交互补充 或使用AD病理（核心C），使用人和小鼠生物测量（核心D）的生物标志物研究，以及 使用人IPSC衍生的细胞和器官模型（核心E）的功能研究。这个U19提案是 由集中保护剂，脂质组学和 关于各种动物和IPSC模型的代谢组学研究，以及人类验尸大脑和液体 生物测量。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 支持分析包括单细胞RNA-seq和Biostatistics的大型数据集的支持 确保科学严谨。核心G还将与管理核心（核心A）紧密合作以维护APOE Web门户网站被指定为EPAAD，知识，资源和数据将与科学共享 社区。核心A还将组织年度APOE研讨会，以促进协作和参与APOE 社区。因此，该U19将推动基于团队的努力来产生基本知识来指导疾病 - 修改AD和其他与衰老相关疾病的疗法。

项目成果

Microglial TREM2 in amyotrophic lateral sclerosis.

• DOI: 10.1002/dneu.22864
• 发表时间: 2022-01
• 期刊: Developmental neurobiology
• 影响因子: 3
• 作者: Xie M;Zhao S;Bosco DB;Nguyen A;Wu LJ
• 通讯作者: Wu LJ

LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4.

• DOI: 10.1172/jci.insight.163822
• 发表时间: 2023-04-10
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Oue, Hiroshi;Yamazaki, Yu;Qiao, Wenhui;Yuanxin, Chen;Ren, Yingxue;Kurti, Aishe;Shue, Francis;Parsons, Tammee M.;Perkerson, Ralph B.;Kawatani, Keiji;Wang, Ni;Starling, Skylar C.;Roy, Bhaskar;Mosneag, Ioana-Emilia;Aikawa, Tomonori;Holm, Marie-Louise;Liu, Chia-Chen;Inoue, Yasuteru;Sullivan, Patrick M.;Asmann, Yan W.;Kim, Betty Y. S.;Bu, Guojun;Kanekiyo, Takahisa
• 通讯作者: Kanekiyo, Takahisa

APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology.

• DOI: 10.1007/s00401-022-02421-8
• 发表时间: 2022-06
• 期刊: Acta neuropathologica
• 影响因子: 12.7

TDP-43 Pathology in Alzheimer's Disease.

• DOI: 10.1186/s13024-021-00503-x
• 发表时间: 2021-12-20
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Meneses A;Koga S;O'Leary J;Dickson DW;Bu G;Zhao N
• 通讯作者: Zhao N

Standardized immunoprecipitation protocol for efficient isolation of native apolipoprotein E particles utilizing HJ15.4 monoclonal antibody.

• DOI: 10.1016/j.xpro.2023.102271
• 发表时间: 2023-06-07
• 期刊: STAR PROTOCOLS
• 作者: O'Leary, Justin;Raulin, Ana-Caroline;Li, Zonghua;Martens, Yuka;Inoue, Yasuteru;Strickland, Michael R.;Han, Xianlin;Holtzman, David M.;Bu, Guojun;Zhao, Na
• 通讯作者: Zhao, Na