ABSTRACT Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 ( PLCG2 ) gene which confers protection against Alzheimer’s disease (AD)-associated cognitive decline. Therefore, PLCG2, which is primarily expressed in immune cells, has become a target of interest for potential therapeutic intervention. The protective allele, known as P522R , has been shown to be hyper-morphic in microglia, increasing phagocytosis of amyloid-beta (Aβ), and increasing the release of inflammatory cytokines. However, the effect of this protective mutation on peripheral tissue-resident macrophages, and the extent to which sex modifies this effect, has yet to be assessed. Herein, we show that peripheral macrophages from wild-type (WT) female and male mice harbor intrinsic differences, with macrophages from females exhibiting less phagocytosis and lysosomal protease activity, as well as a more pro-inflammatory phenotype upon stimulation compared to those from male mice. Furthermore, we demonstrate that the P522R mutation does indeed alter peripheral macrophage function in a sex-dependent manner, with more prominent effects seen in females, including pushing macrophages from females toward an M2 protective phenotype that more closely resembles macrophages from males. These results suggest that the P522R mutation may be partially conferring protection against protein aggregation via activation of peripheral immune cell function and underscore the importance of considering sex as a biological variable when assessing the viability of potential immune system-targeted therapies.

Alzheimer's disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner and confers functional advantage in female mice