Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease.

ABSTRACT: 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 Aβ clearance. The variants bidirectionally modulated disease pathology by

SUBMITTER: Tsai AP 

PROVIDER: S-EPMC10564391 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature