Genetic variants of phospholipase C-g2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease

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 mi-croglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in pla-que-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Ab clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial sub -populations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial re-sponses in AD pathogenesis that can be therapeutically targeted.

Automated summary

Genetic association studies have shown the critical role of microglial immune response in Alzheimer's disease pathogenesis. Two genetic variants of the PLCG2 gene, PLCG2P522R and PLCG2M28L, have been identified to be associated with AD risk. PLCG2P522R reduces the risk while PLCG2M28L increases the risk of AD. These variants modulate microglial responses and contribute to the development of AD.