Human genetic data indicate that microglial dysfunction contributes to the pathology of Alzheimer’s disease (AD), exemplified by the identification of coding variants in triggering receptor expressed on myeloid cells 2 (TREM2) and, more recently, in PLCG2, a phospholipase-encoding gene expressed in microglia. Although studies in mouse models have implicated specific Trem2-dependent microglial functions in AD, the underlying molecular mechanisms and translatability to human disease remain poorly defined. In this study, we used genetically engineered human induced pluripotent stem cell-derived microglia-like cells to show that TREM2 signals through PLCγ2 to mediate cell survival, phagocytosis, processing of neuronal debris, and lipid metabolism. Loss of TREM2 or PLCγ2 signaling leads to a shared signature of transcriptional dysregulation that underlies these phenotypes. Independent of TREM2, PLCγ2 also signals downstream of Toll-like receptors to mediate inflammatory responses. Therefore, PLCγ2 activity regulates divergent microglial functions via distinct TREM2-dependent and -independent signaling and might be involved in the transition to a microglial state associated with neurodegenerative disease.

人类遗传数据表明，小胶质细胞功能障碍有助于阿尔茨海默病 (AD) 的病理学，例如在触发髓细胞 2 ( TREM2 ) 以及最近在PLCG2上表达的受体中的编码变体的鉴定，一种在小胶质细胞中表达的磷脂酶编码基因。尽管对小鼠模型的研究表明 AD 中存在特定的 Trem2 依赖性小胶质细胞功能，但其潜在的分子机制和对人类疾病的可翻译性仍不清楚。在这项研究中，我们使用基因工程人类诱导的多能干细胞衍生的小胶质细胞样细胞来证明 TREM2 通过 PLCγ2 发出信号以介导细胞存活、吞噬作用、神经元碎片的处理和脂质代谢。TREM2 或 PLCγ2 信号传导的丢失导致转录失调的共同特征，这是这些表型的基础。独立于 TREM2，PLCγ2 还向 Toll 样受体的下游发出信号以介导炎症反应。所以，