美国德纳里峰疗法Joseph W. Lewcock和Laralynne Przybyla研究组合作取得新进展。他们发现阿尔茨海默氏病（AD）相关的PLCγ2是髓样细胞2（TREM2）功能和人类小胶质细胞炎症反应所需的信号转导节点。该研究于2020年6月8日发表于《自然—神经科学》。

在这项研究中，他们使用基因工程改造的人诱导多能干细胞来源的小胶质样细胞，来显示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信号的丢失导致这些表型基础的转录失调的共同特征。独立于TREM2，PLCγ2还向Toll样受体下游发出信号以介导炎症反应。因此，PLCγ2活性通过不同的TREM2依赖性和非依赖性信号转导调节不同的小胶质细胞功能，并且可能参与向与神经退行性疾病相关的小胶质细胞状态的转变。

据介绍，人类遗传数据表明，小胶质细胞功能障碍导致了AD的病理，这是通过鉴定在TREM2以及在小胶质细胞PLCG2中表达的磷脂酶编码基因中触发受体的编码变体来鉴定的。尽管在小鼠模型中的研究暗示了AD中特定的Trem2依赖性小胶质细胞功能，但潜在的分子机制和对人类疾病的可翻译性仍然定义不清。

附：英文原文

Title: Alzheimer’s-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia

Author: Benjamin J. Andreone, Laralynne Przybyla, Ceyda Llapashtica, Anil Rana, Sonnet S. Davis, Bettina van Lengerich, Karin Lin, Ju Shi, Yuan Mei, Giuseppe Astarita, Gilbert Di Paolo, Thomas Sandmann, Kathryn M. Monroe, Joseph W. Lewcock

Issue&Volume: 2020-06-08

Abstract: 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.

DOI: 10.1038/s41593-020-0650-6

Source: https://www.nature.com/articles/s41593-020-0650-6