The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model.
The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model.
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DOI：
10.1002/alz.12577
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发表时间：
2022-10
期刊：
影响因子：
--
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中科院分区：
文献类型：
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由小胶质细胞表达的PLCG 2的P522 R变体与阿尔茨海默病（AD）的风险降低相关。然而，这种保护性突变对小胶质细胞对AD病理反应的影响仍然未知。通过移植PLCG 2-P522 R或同基因野生型人诱导多能干细胞小胶质细胞产生嵌合AD和野生型小鼠。在7月龄时，进行单细胞和批量RNA测序以及组织学分析。PLCG 2-P522 R变体诱导小胶质细胞人类白细胞抗原（HLA）表达显著增加，并诱导抗原呈递、趋化因子信号传导和T细胞增殖途径。对免疫完整的AD小鼠的检查进一步证明，PLCG 2-P522 R变体促进了CD 8 + T细胞向大脑的募集。这些数据提供了第一个证据，即PLCG 2-P522 R变体增加了小胶质细胞招募T细胞和呈递抗原的能力，促进了最近在AD患者大脑中被证明减少的小胶质细胞转录状态。
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.
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影响因子：
16.6
作者：
McQuade A;Kang YJ;Hasselmann J;Jairaman A;Sotelo A;Coburn M;Shabestari SK;Chadarevian JP;Fote G;Tu CH;Danhash E;Silva J;Martinez E;Cotman C;Prieto GA;Thompson LM;Steffan JS;Smith I;Davtyan H;Cahalan M;Cho H;Blurton-Jones M
通讯作者：
Blurton-Jones M
影响因子：
--
作者：
Lu RC;Yang W;Tan L;Sun FR;Tan MS;Zhang W;Wang HF;Tan L
通讯作者：
Tan L
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
5
作者：
Handunnetthi, L.;Ramagopalan, S. V.;Ebers, G. C.;Knight, J. C.
通讯作者：
Knight, J. C.
影响因子：
14.9
作者：
Khan A;Fornes O;Stigliani A;Gheorghe M;Castro-Mondragon JA;van der Lee R;Bessy A;Chèneby J;Kulkarni SR;Tan G;Baranasic D;Arenillas DJ;Sandelin A;Vandepoele K;Lenhard B;Ballester B;Wasserman WW;Parcy F;Mathelier A
通讯作者：
Mathelier A