| First Author | Tsai AP | Year | 2023 |
| Journal | Immunity | Volume | 56 |
| Issue | 9 | Pages | 2121-2136.e6 |
| PubMed ID | 37659412 | Mgi Jnum | J:348145 |
| Mgi Id | MGI:7528592 | Doi | 10.1016/j.immuni.2023.08.008 |
| Citation | Tsai AP, et al. (2023) Genetic variants of phospholipase C-gamma2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease. Immunity 56(9):2121-2136.e6 |
| abstractText | Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2(P522R), is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2(M28L), that confers an increased AD risk. PLCG2(P522R) attenuated disease in an amyloidogenic murine AD model, whereas PLCG2(M28L) exacerbated the plaque burden associated with altered phagocytosis and Abeta clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2(M28L) as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted. |
