Dynamic immune cell landscape in late-onset Alzheimer's disease: role of ApoE-mediated microglial lipid metabolism

晚发性阿尔茨海默病的动态免疫细胞景观：ApoE 介导的小胶质细胞脂质代谢的作用

• 批准号: 10370588
• 负责人: I-Chen Ivorine Yu
• 金额: $ 45.1万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370588
• 关键词: Affect; Affinity; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Antibodies; Apolipoprotein E; Binding; Biochemical; Biological Assay; Blood; Blood Vessels; Brain; Cell Lineage; Cell Surface Proteins; Cell membrane; Cell physiology; Cells; Cholesterol; Chronic; Cognitive deficits; Complex; Dementia; Development; Dietary Fats; Dimensions; Disease; Disease Progression; E protein; Elderly; Environmental Risk Factor; Exhibits; Gene Activation; Genes; Genetic; Genetic Risk; Genetic Transcription; Genotype; Health; Hemostatic function; Heterogeneity; Homeostasis; Human; Immune; Immunity; Impaired cognition; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Investigation; Knock-in Mouse; Knowledge; Late Onset Alzheimer Disease; Link; Lipids; Measurement; Measures; Mediating; Membrane Microdomains; Membrane Proteins; Metabolism; Microglia; Molecular; Molecular Profiling; Mus; Myelogenous; Nerve Degeneration; Obesity; Oligonucleotides; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Phospholipids; Play; Population; Production; Protein Isoforms; Proteins; RNA; Resolution; Risk; Role; Senile Plaques; Signal Pathway; Sphingomyelins; T-Lymphocyte; TLR2 gene; TREM2 gene; Testing; Tissues; Triglycerides; Tumor-infiltrating immune cells; United States; Up-Regulation; Work; apolipoprotein E-3; apolipoprotein E-4; combat; cytokine; diet-induced obesity; fatty acid metabolism; gene environment interaction; genetic association; genetic variant; high risk; immune function; individualized medicine; inflammatory milieu; innovation; insight; lifestyle intervention; lipid metabolism; lipidome; lipidomics; mRNA sequencing; macrophage; middle age; monocyte; multimodality; neuroinflammation; neurotoxicity; novel; novel therapeutic intervention; obese person; particle; prevent; recruit; single-cell RNA sequencing; therapeutically effective; transcriptome; transcriptomics

Project Summary Alzheimer's disease (AD) is the leading cause of dementia in older adults and affects over 5 million individuals in the United States alone. The more common form of AD, late-onset, is a multifactorial disorder in which ApoE4 is the most potent genetic risk. The ApoE4 isoform is also linked to midlife obesity which can cause cognitive decline in older adults. Obesity is a condition of chronic inflammation characterized by activated immune cells and increased inflammatory mediators in the blood. Recently, through genetic association studies, microglia and other myeloid origin immune cells have emerged as crucial players in AD pathogenesis. Single-cell RNA sequencing analysis in mouse and human AD brains has identified a distinct subset associated with amyloid plaques and the upregulation of ApoE in microglia. Therefore, further investigation of microglia and other immune cells is needed to understand how these cells are affected by ApoE4 isoform and obesity contributing to late- onset AD progression. Our objective in this R21 project is to explore the gene-environment interactions between ApoE4 and obesity in regulating phenotypic plasticity of microglia and peripheral immune cells. This project aims to identify molecular pathways that could restore healthy immune function to treat late-onset AD. Our Specific Aims are to (1) Assess dynamic changes of brain immune cell populations influenced by ApoE4 and diet-induced obesity in human ApoE isoform knock-in mice; (2) Identify altered lipid metabolism in ApoE4 microglia that modulates the phenotypic plasticity. The successful completion of this project will reveal the multifaceted roles of ApoE4 in modulating immunometabolism. Moreover, it will provide a strong rationale for lifestyle interventions or individualized therapeutic strategies for late-onset AD in ApoE4 carriers.

项目概要 阿尔茨海默病 (AD) 是导致老年人痴呆的主要原因，影响超过 500 万人 仅在美国。 AD 更常见的形式是晚发型，是一种多因素疾病，其中 ApoE4 是最有效的遗传风险。 ApoE4 同工型也与中年肥胖有关，这可能导致认知障碍 老年人的下降。肥胖是一种慢性炎症，其特征是免疫细胞被激活 并增加血液中的炎症介质。最近，通过遗传关联研究，小胶质细胞和 其他骨髓来源的免疫细胞已成为 AD 发病机制的关键参与者。单细胞RNA 小鼠和人类 AD 大脑的测序分析发现了与淀粉样蛋白相关的独特子集 斑块和小胶质细胞中 ApoE 的上调。因此，进一步研究小胶质细胞和其他免疫细胞 需要细胞来了解这些细胞如何受到 ApoE4 同工型的影响以及肥胖如何导致晚期 AD 发病进展。我们在这个 R21 项目中的目标是探索基因与环境之间的相互作用 ApoE4 和肥胖调节小胶质细胞和外周免疫细胞的表型可塑性。该项目旨在 以确定可以恢复健康免疫功能以治疗迟发性 AD 的分子途径。我们的具体 目的是 (1) 评估受 ApoE4 和饮食诱导影响的脑免疫细胞群的动态变化 人类 ApoE 亚型敲入小鼠的肥胖； (2) 确定 ApoE4 小胶质细胞中脂质代谢的改变 调节表型可塑性。该项目的成功完成将揭示多方面的作用 ApoE4 在调节免疫代谢中的作用。此外，它将为生活方式干预提供强有力的理由 或 ApoE4 携带者迟发性 AD 的个体化治疗策略。