| First Author | Andreone BJ | Year | 2020 |
| Journal | Nat Neurosci | Volume | 23 |
| Issue | 8 | Pages | 927-938 |
| PubMed ID | 32514138 | Mgi Jnum | J:298292 |
| Mgi Id | MGI:6478735 | Doi | 10.1038/s41593-020-0650-6 |
| Citation | Andreone BJ, et al. (2020) Alzheimer's-associated PLCgamma2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci 23(8):927-938 |
| abstractText | 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 PLCgamma2 to mediate cell survival, phagocytosis, processing of neuronal debris, and lipid metabolism. Loss of TREM2 or PLCgamma2 signaling leads to a shared signature of transcriptional dysregulation that underlies these phenotypes. Independent of TREM2, PLCgamma2 also signals downstream of Toll-like receptors to mediate inflammatory responses. Therefore, PLCgamma2 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. |
