| Autor: |
Andy P. Tsai, Chuanpeng Dong, Peter Bor-Chian Lin, Adrian L. Oblak, Gonzalo Viana Di Prisco, Nian Wang, Nicole Hajicek, Adam J. Carr, Emma K. Lendy, Oliver Hahn, Micaiah Atkins, Aulden G. Foltz, Jheel Patel, Guixiang Xu, Miguel Moutinho, John Sondek, Qisheng Zhang, Andrew D. Mesecar, Yunlong Liu, Brady K. Atwood, Tony Wyss-Coray, Kwangsik Nho, Stephanie J. Bissel, Bruce T. Lamb, Gary E. Landreth |
| Rok vydání: |
2022 |
| Popis: |
SummaryGenetic 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 ofPLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. We report the identification of aPLCG2variant,PLCG2M28L, associated with loss-of-function and confers increased AD risk. PLCG2P522Rattenuates disease in an amyloidogenic murine AD model, whereasPLCG2M28Lexacerbates 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 PLCG2M28Las a new AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.Graphical abstractHighlightsA 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 pathogenesisConversely, PLCG2P522R, a protective PLCG2 variant, attenuates AD pathogenesisThe PLCG2 variants uniquely alter the microglial transcriptome and phenotypes |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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