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，影响超过500万人 仅在美国。AD的更常见形式，迟发性，是一种多因素疾病，其中ApoE 4 是最大的遗传风险ApoE 4亚型也与中年肥胖有关，中年肥胖可导致认知功能障碍。 老年人下降。肥胖是一种慢性炎症状态，其特征是免疫细胞被激活 以及血液中炎症介质的增加。最近，通过遗传关联研究，小胶质细胞和 其它髓源性免疫细胞已成为AD发病机制中的关键参与者。单细胞RNA 对小鼠和人类AD大脑的测序分析已经确定了与淀粉样蛋白相关的一个独特的子集 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 需要了解这些细胞是如何受到ApoE 4同种型和肥胖的影响，从而导致晚期- AD进展发作。我们在这个R21项目中的目标是探索基因与环境的相互作用， ApoE 4与肥胖对小胶质细胞和外周免疫细胞表型可塑性的调节该项目旨在 以确定可以恢复健康免疫功能的分子途径来治疗迟发性AD。我们的具体 目的是（1）评估ApoE 4和饮食诱导的脑免疫细胞群的动态变化 人ApoE同种型基因敲入小鼠中的肥胖;（2）鉴定ApoE 4小胶质细胞中改变的脂质代谢， 调节表型可塑性。该项目的成功完成将揭示多方面的作用 ApoE 4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ApoE 4携带者中迟发性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.