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The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model
Author(s) -
Claes Christel,
England Whitney E.,
Danhash Emma P.,
Kiani Shabestari Sepideh,
Jairaman Amit,
Chadarevian Jean Paul,
Hasselmann Jonathan,
Tsai Andy P.,
Coburn Morgan A.,
Sanchez Jessica,
Lim Tau En,
Hidalgo Jorge L. S.,
Tu Christina,
Cahalan Michael D.,
Lamb Bruce T.,
Landreth Gary E.,
Spitale Robert C.,
BlurtonJones Mathew,
Davtyan Hayk
Publication year - 2022
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12577
Subject(s) - microglia , biology , antigen presentation , immune system , antigen , immunology , t cell , inflammation
The P522R variant of PLCG2, expressed by microglia, is associated with reduced risk of Alzheimer's disease (AD). Yet, the impact of this protective mutation on microglial responses to AD pathology remains unknown. Chimeric AD and wild‐type mice were generated by transplanting PLCG2‐P522R or isogenic wild‐type human induced pluripotent stem cell microglia. At 7 months of age, single‐cell and bulk RNA sequencing, and histological analyses were performed. The PLCG2‐P522R variant induced a significant increase in microglial human leukocyte antigen (HLA) expression and the induction of antigen presentation, chemokine signaling, and T cell proliferation pathways. Examination of immune‐intact AD mice further demonstrated that the PLCG2‐P522R variant promotes the recruitment of CD8 + T cells to the brain. These data provide the first evidence that the PLCG2‐P522R variant increases the capacity of microglia to recruit T cells and present antigens, promoting a microglial transcriptional state that has recently been shown to be reduced in AD patient brains.