Alzheimer's-associated PLC¥ã2 Is a Signaling Node Required for Both TREM2 Function and the Inflammatory Response in Human Microglia
Benjamin J Andreone 1, Laralynne Przybyla 2, Ceyda Llapashtica 1, Anil Rana 1, Sonnet S Davis 1, Bettina van Lengerich 1, Karin Lin 1, Ju Shi 1, Yuan Mei 1, Giuseppe Astarita 1, Gilbert Di Paolo 1, Thomas Sandmann 1, Kathryn M Monroe 1, Joseph W Lewcock 3 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 PLC¥ã2 to mediate cell survival, phagocytosis, processing of neuronal debris, and lipid metabolism. Loss of TREM2 or PLC¥ã2 signaling leads to a shared signature of transcriptional dysregulation that underlies these phenotypes. Independent of TREM2, PLC¥ã2 also signals downstream of Toll-like receptors to mediate inflammatory responses. Therefore, PLC¥ã2 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.