TREM2 T204A突变增强小胶质细胞Aβ清除能力并促进TREM2-DAP12-SYK信号通路活化

doi:10.16352/j.issn.1001-6325.2026.08.1036

基础医学与临床 ›› 2026, Vol. 46 ›› Issue (8): 1036-1041.doi: 10.16352/j.issn.1001-6325.2026.08.1036

TREM2 T204A突变增强小胶质细胞Aβ清除能力并促进TREM2-DAP12-SYK信号通路活化

牛琪, 王晴钰, 朱宛宛^*

中国医学科学院北京协和医学院基础医学研究所生物化学与分子生物学系,北京 100005

收稿日期:2026-04-03 修回日期:2026-05-07 发布日期:2026-07-22
通讯作者: ^*ww.zhu@ibms.pumc.edu.cn
基金资助:
载人航天工程航天医学实验领域项目(HYZHXMN01001);国家自然科学基金重大项目(32293213)

TREM2 T204A mutation enhances the ability of microglia to clear Aβ and promotes the activation of the TREM2-DAP12-SYK signaling pathway

NIU Qi, WANG Qingyu, ZHU Wanwan^*

Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China

Received:2026-04-03 Revised:2026-05-07 Published:2026-07-22
Contact: ^*ww.zhu@ibms.pumc.edu.cn

摘要/Abstract

摘要： 目的探究髓系触发受体2(TREM2)第204位苏氨酸突变为丙氨酸(T204A)对小胶质细胞吞噬功能及TREM2-DAP12-SYK信号通路活性的影响。方法构建野生型及突变体表达质粒并转染293T细胞系、HMC3小胶质细胞系。通过免疫荧光和Western blot检测TREM2的细胞定位及蛋白表达水平。通过Aβ处理建立吞噬模型,ELISA检测细胞上清中Aβ残余水平以评估细胞清除能力。利用免疫共沉淀(Co-IP)分析TREM2与DAP12相互作用,并通过Western blot检测SYK及AKT的磷酸化水平。结果本研究发现3个TREM2编码区单核苷酸多态性,其中2个位于同源异构体2(isoform2),1个位于同源异构体1(isoform1)。3个SNP均未影响蛋白表达及定位。与野生组相比,仅SNP1(T204A)突变显著降低细胞上清中Aβ残余(P＜0.05),提示其增强HMC3细胞对A的吞噬能力。进一步分析发现,T204A突变增强TREM2与DAP12结合,并伴随SYK磷酸化升高,提示下游信号通路被激活。结论在3个SNP中,TREM2 T204A为功能增强型突变。该突变可增强TREM2-DAP12复合体形成并促进SYK信号活化,从而提高小胶质细胞Aβ清除能力。

关键词: 髓系细胞触发受体2(TREM2), 小胶质细胞, 阿尔茨海默病, 神经免疫

Abstract: Objective To investigate the effects of the T204A variant in triggering receptor expressed on myeloid cells 2(TREM2) on microglial phagocytic function and the activity of the TREM2-DAP12-SYK signaling pathway. Methods Wild-type and mutant constructs were expressed in 293T and HMC3 microglia. Protein expression and localisation were assessed by immunofluorescence and Western blot. Aβ clearance-related capacity was evaluated by measuring residual Aβ levels in the supernatant using ELISA. TREM2-DAP12 interaction was analysed by Co-IP, and SYK/AKT phosphorylation was examined by Western blot. Results This study identified three SNPs in the TREM2 coding region, two of which were located in isoform2 and one in isoform1. None of the three SNPs affected TREM2 expression or localisation. Only T204A significantly reduced residual Aβ levels in the supernatant(P＜0.05), indicating enhanced Aβ clearance-related capacity. Mechanistically, T204A increased TREM2-DAP12 interaction and was associated with elevated SYK phosphorylation. Conclusions TREM2 T204A is a gain-of-function variant that enhances TREM2-DAP12 complex formation and is associated with increased SYK signaling and Aβ clearance in microglia.

Key words: TREM2, microglia, Alzheimer′s disease, neuroimmunity

中图分类号:

牛琪, 王晴钰, 朱宛宛. TREM2 T204A突变增强小胶质细胞Aβ清除能力并促进TREM2-DAP12-SYK信号通路活化[J]. 基础医学与临床, 2026, 46(8): 1036-1041.

NIU Qi, WANG Qingyu, ZHU Wanwan. TREM2 T204A mutation enhances the ability of microglia to clear Aβ and promotes the activation of the TREM2-DAP12-SYK signaling pathway[J]. Basic & Clinical Medicine, 2026, 46(8): 1036-1041.

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TREM2 T204A突变增强小胶质细胞Aβ清除能力并促进TREM2-DAP12-SYK信号通路活化

TREM2 T204A mutation enhances the ability of microglia to clear Aβ and promotes the activation of the TREM2-DAP12-SYK signaling pathway

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