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） 该 U19 项目的总体目标是全面了解以下疾病的生物学和病理学： 载脂蛋白 E (apoE) 在衰老和阿尔茨海默病 (AD) 中的作用，为治疗策略提供参考。 APOE 基因 (APOE4) 是 AD 最强的遗传风险因素，影响 50-70% 的 AD 患者，而 与常见的 ε3 等位基因相比，ε2 等位基因具有保护作用，APOE4 也是与年龄相关的强大危险因素。 认知能力下降和血管性认知障碍整合现有知识并解决关键差距， 我们提出了一个统一的ApoE级联假说，即结构差异和相关的生物化学 三种 apoE 亚型之间的特性引发了它们对细胞级联事件的不同影响。 和系统水平最终影响包括 AD 在内的衰老相关致病性疾病。 组建了一支多学科团队，以整合多个机构的专业知识和资源。 整合五个互动项目和七个强大的核心，我们将为 apoE 相关衰老创建一个纽带 项目 1 将进行研究，与更广泛的科学界分享知识、专业知识和资源。 与 Core B 密切合作，解决三种 apoE 亚型的结构和生化特性， 项目 2、3 和 4 将交互研究 apoE 异构体如何产生功能结果的见解。 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， 使用条件小鼠模型和系统研究 AD 相关病理学以及细胞和分子途径 - 这些研究将产生细胞类型特异性的 apoE/脂蛋白颗粒。 通过体内微透析收集的用于结构和生化研究的项目5将进行基因组研究。 项目 2-5 中将进行遗传分析，以确定 AD 发病时与 APOE 相关的年龄的修饰因素。 使用来自健康衰老研究的死后大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本进行生物标志物研究（核心 D），以及 使用人类 iPSC 衍生的细胞和类器官模型进行功能研究（核心 E）。 由全面的多组学核心（Core F）支持，用于集中蛋白质组学、脂质组学和 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 生物样本。生物信息学、生物统计学和数据管理核心（核心 G）将提供关键的信息。 支持分析大型数据集，包括来自单细胞 RNA-seq 的数据集和生物统计学支持 确保科学性 核心 G 还将与行政核心（核心 A）密切合作，以维持 ApoE。 指定为 EPAAD 的门户网站，其中知识、资源和数据将与科学界共享 Core A 还将组织年度 ApoE 研讨会，以促进合作并吸引 ApoE 参与。 因此，这个 U19 将推动基于团队的努力，以产生指导疾病的基本知识。 修改 AD 和其他衰老相关疾病的治疗方法。

项目成果

Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms.

载脂蛋白 E4 在无脂和脂结合形式中具有广泛的构象异质性。

• 发表时间: 2023-02-14
• 影响因子: 11.1
• 作者: Stuchell;Zimmerman, Maxwell I;Miller, Justin J;Mallimadugula, Upasana L;Incicco, J Jeremías;Roy, Debjit;Smith, Louis G;Cubuk, Jasmine;Baban, Berevan;DeKoster, Gregory T;Frieden, Carl;Bowman, Gregory R;Soranno, Andrea
• 通讯作者: Soranno, Andrea

Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination.

apoE2 和 apoE4 对脱髓鞘反应中小胶质细胞活化和脂质代谢的相反作用。

• 发表时间: 2022-11-23
• 影响因子: 15.1
• 作者: Wang, Na;Wang, Minghui;Jeevaratnam, Suren;Rosenberg, Cassandra;Ikezu, Tadafumi C;Shue, Francis;Doss, Sydney V;Alnobani, Alla;Martens, Yuka A;Wren, Melissa;Asmann, Yan W;Zhang, Bin;Bu, Guojun;Liu, Chia
• 通讯作者: Liu, Chia

SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome.

SARS-CoV-2 的模拟达到百亿亿级，可以预测蛋白质组中剧烈的尖峰开口和神秘口袋。

• 发表时间: 2021-07
• 影响因子: 21.8
• 作者: Zimmerman, Maxwell I;Porter, Justin R;Ward, Michael D;Singh, Sukrit;Vithani, Neha;Meller, Artur;Mallimadugula, Upasana L;Kuhn, Catherine E;Borowsky, Jonathan H;Wiewiora, Rafal P;Hurley, Matthew F D;Harbison, Aoife M;Fogarty, Carl A;Coffland
• 通讯作者: Coffland

Suppression of Wnt/β-Catenin Signaling Is Associated with Downregulation of Wnt1, PORCN, and Rspo2 in Alzheimer's Disease.

Wnt/β-连环蛋白信号传导的抑制与阿尔茨海默病中 Wnt1、PORCN 和 Rspo2 的下调相关。

• 发表时间: 2023-01
• 影响因子: 5.1
• 作者: Macyczko, Jesse R;Wang, Na;Zhao, Jing;Ren, Yingxue;Lu, Wenyan;Ikezu, Tadafumi C;Zhao, Na;Liu, Chia;Bu, Guojun;Li, Yonghe
• 通讯作者: Li, Yonghe

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

PSEN1 E280A 哥伦比亚亲属中痴呆症发病年龄的遗传关联。

• 发表时间: 2023-09
• 作者: Cochran, Jesse Nicholas;Acosta;Esposito, Bianca T;Madrigal, Lucia;Aguillón, David;Giraldo, Margarita M;Taylor, Jared W;Bradley, Joseph;Fulton;Andrews, Shea J;Acosta;Alzate, Diana;Garcia, Gloria P;Pi
• 通讯作者: Pi