Genetic Variants of Phospholipase C-γ2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimer’s Disease

Summary 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 acts 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. We report the identification of a PLCG2 variant, PLCG2 M28 L , associated with loss-of-function and confers increased AD risk. PLCG2 P522R attenuates disease in an amyloidogenic murine AD model, whereas PLCG2 M28L exacerbates the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulate disease pathology by inducing distinct transcriptional programs that identify microglial subpopulations associated with protective or detrimental phenotypes. In summary, these findings identify PLCG2 M28L as a new AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted. Graphical abstract Highlights A genetic variant of PLCG2, M28L, is associated with an increased risk for Alzheimer’s disease (AD) In an amyloidogenic AD mouse model, PLCG2M28L exacerbates disease pathogenesis Conversely, PLCG2P522R, a protective PLCG2 variant, attenuates AD pathogenesis The PLCG2 variants uniquely alter the microglial transcriptome and phenotypes