Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call 'lipid-droplet-accumulating microglia' (LDAM), are defective in phagocytosis, produce high levels of reactive oxygen species and secrete proinflammatory cytokines. RNA-sequencing analysis of LDAM revealed a transcriptional profile driven by innate inflammation that is distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin (GRN), are causes of autosomal-dominant forms of human neurodegenerative diseases. We therefore propose that LDAM contribute to age-related and genetic forms of neurodegeneration.

中文翻译：

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积累脂滴的小胶质细胞代表衰老大脑中的功能失调和促炎状态。

随着年龄的增长，小胶质细胞逐渐被激活并看似功能失调，遗传研究已将这些细胞与越来越多的神经退行性疾病的发病机制联系起来。在这里，我们报告了随着小鼠和人类大脑衰老，小胶质细胞中脂滴的显着积累。这些细胞，我们称之为“脂滴累积小胶质细胞”（LDAM），在吞噬作用方面存在缺陷，产生高水平的活性氧并分泌促炎细胞因子。LDAM 的 RNA 测序分析揭示了一种由先天炎症驱动的转录谱，这与先前报道的小胶质细胞状态不同。一个公正的 CRISPR-Cas9 筛选确定了脂滴形成的遗传修饰物；令人惊讶的是，其中一些基因的变体，包括颗粒蛋白前体 (GRN)，是人类神经退行性疾病的常染色体显性形式的原因。因此，我们提出 LDAM 有助于年龄相关和遗传形式的神经变性。