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

项目摘要 阿尔茨海默病(AD)是老年人痴呆症的主要原因，影响着500多万人 仅在美国。更常见的AD形式是晚发性，是一种多因素障碍，其中ApoE4 是最大的遗传风险。ApoE4亚型也与中年肥胖症有关，中年肥胖症可导致认知能力 老年人的死亡率下降。肥胖是一种以免疫细胞活化为特征的慢性炎症状态。 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 其他髓系来源的免疫细胞已经成为AD发病机制中的关键角色。单细胞RNA 在小鼠和人类AD脑中的测序分析发现了与淀粉样蛋白相关的一个独特的亚群 斑块与小胶质细胞载脂蛋白E的上调因此，对小胶质细胞等免疫功能的进一步研究 需要细胞来理解ApoE4亚型和肥胖是如何影响这些细胞的- 开始出现阿尔茨海默病进展。我们在R21项目中的目标是探索基因-环境之间的相互作用 载脂蛋白E4和肥胖对小胶质细胞和外周免疫细胞表型可塑性的调节作用。这个项目的目的是 寻找可以恢复健康免疫功能的分子途径来治疗晚发性AD。我们的特定 目的是(1)评估载脂蛋白E4和饮食诱导的脑免疫细胞群的动态变化 人ApoE亚型敲除小鼠的肥胖；(2)鉴定ApoE4小胶质细胞脂代谢的改变 调节表型可塑性。该项目的成功完成将揭示出多方面的作用 载脂蛋白E4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 或针对ApoE4携带者的晚发性AD的个体化治疗策略。

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.