Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.

中文翻译：

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TREM2-APOE途径驱动神经退行性疾病中功能失调的小胶质细胞的转录表型。

小胶质细胞在维持脑稳态中起着关键作用，但在神经退行性疾病中失去稳态功能。我们从肌萎缩性侧索硬化症（ALS），多发性硬化症（MS）和阿尔茨海默氏病（AD）以及神经胶质β-淀粉样蛋白（Aβ）斑块周围的小胶质细胞模型中鉴定了特定的载脂蛋白E（APOE）依赖性分子标记在AD患者的大脑中。凋亡神经元吞噬作用后，APOE途径介导从稳态转移到神经变性小胶质细胞表型。TREM2（在髓样细胞2上表达的触发受体）诱导APOE信号传导，并靶向TREM2-APOE途径在ALS和AD小鼠模型中恢复了小胶质细胞的稳态标志，并防止了神经退行性急性模型中的神经元丢失。APOE介导的神经退行性小胶质细胞失去了致耐受功能。我们的工作确定了TREM2-APOE途径是神经退行性疾病中小胶质细胞功能表型的主要调节剂，并且是可以帮助体内平衡小胶质细胞恢复的新靶标。