ATAC-seq of microglia from 3-, 14- and 24-month-old female mouse brains treated by LPS or PBS. ATAC-seq of microglia from 3-, 14- and 24-month-old female mouse brains treated by LPS or PBS

Microglia are important immune cells in the brain. Microglia undergo a series of alterations during aging and increase the susceptibility to brain dysfunctions. However, the characteristics of microglia during the aging process are not fully understood. In this study, we mapped transcriptional and epigenetic profiles of microglia from 3- to 24-month-old mice. We observed unexpected gender divergences and identified age-dependent microglia (ADEM) genes in the aging process. We then compared characteristics between microglial aging and activation. To dissect the function of aged microglia excluding the influence from other aged brain cells, we established an accelerated microglial turnover model without directly affecting other brain cells. By this model, we achieved aged microglia in non-aged brains and confirmed that aged microglia per se contribute to cognitive decline. Collectively, we provide a comprehensive resource to decode the aging process of microglia, shedding light on how microglia maintain brain functions. Overall design: After administration of PBS or LPS for 1.5 hours, microglia from 3-month, 14-month, and 24-month female mouse brains were purified for sequencing.

小胶质细胞（Microglia）是大脑中重要的免疫细胞。其在衰老过程中会发生一系列改变，并会提升大脑功能障碍的易感性。然而，目前学界对衰老进程中小胶质细胞的特征尚未完全明晰。本研究中，我们对3月龄至24月龄小鼠的小胶质细胞进行了转录组与表观基因组谱的绘制，观察到了未曾预料到的性别差异，并鉴定出了衰老过程中的年龄依赖性小胶质细胞（Age-Dependent Microglia, ADEM）基因。随后我们对比了小胶质细胞衰老与激活的特征差异。为排除其他衰老脑细胞的干扰以剖析衰老小胶质细胞的功能，我们构建了一种可加速小胶质细胞更新、且不会直接影响其他脑细胞的模型。借助该模型，我们在未衰老的大脑中获得了衰老状态的小胶质细胞，并证实衰老小胶质细胞本身即可导致认知功能衰退。综上，本研究提供了一套可用于解析小胶质细胞衰老过程的综合性资源，为阐明小胶质细胞维持大脑功能的机制提供了新的研究视角。实验设计：分别获取3月龄、14月龄及24月龄雌性小鼠脑组织中的小胶质细胞，经磷酸盐缓冲液（Phosphate Buffered Saline, PBS）或脂多糖（Lipopolysaccharide, LPS）处理1.5小时后，对其进行纯化并开展测序。