Demystifying Microglia in Aging and Alzheimer's Disease

炎症已经成为大多数神经退行性疾病的公认组成部分，包括 阿尔茨海默病(AD)。直到最近，我们还没有可靠地分离常驻脑小胶质细胞的工具。 从外周髓系细胞中提取，描绘它们在大脑中的功能。在这份提案中，我们将把 不同的髓系细胞群，如常驻脑小胶质细胞和外周血单核细胞，使用优雅 单细胞下一代RNA测序(scRNA-Seq)。我们将确定这些神经的反应 免疫成分对生理性脑活动和神经退变有促进作用。使用新的小鼠模型 条件性靶向，我们将操纵AD风险基因，特别是在大脑小胶质细胞，并表征 野生型小鼠和类阿尔茨海默病小鼠在单细胞和全动物水平上的后果 病理学。重要的是，我们将把这些基因表达谱与从500多个井获得的基因表达谱进行比较 研究了健康人和AD患者，以评估不同单核细胞表型与 人类阿尔茨海默病的发病和进展。

Inflammation has become a well-recognized component of most neurodegenerative disorders, including Alzheimer's disease (AD). Until recently, we did not have the tools to reliably separate resident brain microglia from peripheral myeloid cells to delineate their functions in the brain. In this proposal, we will characterize different myeloid cell populations, such as resident brain microglia and peripheral monocytes, using elegant single-cell next-generation RNA sequencing (scRNA-Seq). We will determine the response of these neural immune components to physiological brain activity and neurodegeneration. Using novel models of mice with conditional targeting, we will manipulate AD risk genes specifically in brain microglia, and characterize the consequences, at both the single-cell and whole-animal level, in wildtype mice and mouse models of AD-like pathology. Importantly, we will compare these gene expression profiles to those obtained from over 500 well- studied healthy individuals and AD patients to assess the relevance of different monocyte phenotypes to the onset and progression of human AD.