Department of Neurosurgery, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Fudan University, Shanghai, China.
Department of Neurology, Zhongshan Hospital, Department of Laboratory Animal Science, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
Nat Aging. 2023 Oct;3(10):1288-1311. doi: 10.1038/s43587-023-00479-x. Epub 2023 Sep 11.
As important immune cells, microglia undergo a series of alterations during aging that increase the susceptibility to brain dysfunctions. However, the longitudinal characteristics of microglia remain poorly understood. In this study, we mapped the transcriptional and epigenetic profiles of microglia from 3- to 24-month-old mice. We first discovered unexpected sex differences and identified age-dependent microglia (ADEM) genes during the aging process. We then compared the features of aging and reactivity in female microglia at single-cell resolution and epigenetic level. To dissect functions 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-like microglia in non-aged brains and confirmed that aged-like microglia per se contribute to cognitive decline. Collectively, our work provides a comprehensive resource for decoding the aging process of microglia, shedding light on how microglia maintain brain functions.
作为重要的免疫细胞，小胶质细胞在衰老过程中经历了一系列改变，从而增加了大脑功能障碍的易感性。然而，小胶质细胞的纵向特征仍知之甚少。在这项研究中，我们绘制了来自 3 至 24 个月大的小鼠的小胶质细胞的转录组和表观遗传图谱。我们首先发现了意想不到的性别差异，并在衰老过程中鉴定了与年龄相关的小胶质细胞（ADEM）基因。然后，我们在单细胞分辨率和表观遗传水平上比较了雌性小胶质细胞衰老和反应性的特征。为了排除其他衰老脑细胞的影响来剖析衰老小胶质细胞的功能，我们建立了一种加速小胶质细胞更替的模型，而不直接影响其他脑细胞。通过该模型，我们在未衰老的大脑中实现了类似衰老的小胶质细胞，并证实了类似衰老的小胶质细胞本身会导致认知能力下降。总之，我们的工作为解码小胶质细胞的衰老过程提供了一个全面的资源，揭示了小胶质细胞如何维持大脑功能。
