Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2).
Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2).
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β 淀粉样蛋白通过与髓样细胞 2 (TREM2) 上表达的触发受体结合来调节小胶质细胞反应。
DOI：
10.1186/s13024-018-0247-7
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发表时间：
2018-03-27
影响因子：
15.1
通讯作者：
Chen XF
中科院分区：
文献类型：
--
作者：
Zhong L;Wang Z;Wang D;Wang Z;Martens YA;Wu L;Xu Y;Wang K;Li J;Huang R;Can D;Xu H;Bu G;Chen XF
TREM 2是在小胶质细胞中特异性表达的先天性免疫受体。据报道，TREM 2的编码变异会增加阿尔茨海默病（AD）和其他神经退行性疾病的风险。虽然多项研究支持TREM 2在小胶质细胞向淀粉样斑块募集中的作用，但尚未确定调节TREM 2依赖性小胶质细胞反应的化学引诱因子。通过互补方法（包括固相结合、表面等离子体共振和免疫沉淀测定）检测寡聚淀粉样蛋白-β 1-42（oAβ1-42）与TREM 2的潜在结合。通过分析原代小胶质细胞中Syk和Akt的磷酸化以及报告细胞系统中TREM 2介导的信号传导，检查了oAβ1-42激活TREM 2信号传导途径的能力。最后，通过检查对体外小胶质细胞迁移的影响和体内oA β1-42-TREM 2相互作用对oAβ1-42脑区周围聚集的影响，检测了oAβ1 - 42-TREM 2相互作用的功能结局。我们发现oAβ1-42与TREM 2以高亲和力结合并激活TREM 2依赖的信号通路。单体A β和乱序Aβ均不与TREM 2结合，支持oAβ和TREM 2之间的特异性相互作用。TREM 2的疾病相关突变降低了其与oAβ1-42的结合亲和力。此外，我们在TREM 2的残基31-91中鉴定了几个带正电荷的氨基酸，这些氨基酸对其与oAβ1-42的相互作用至关重要。重要的是，oAβ1-42以TREM 2依赖性方式促进体外小胶质细胞迁移和体内聚集。我们的数据建立了oAβ1-42（AD的主要病理成分）和TREM 2（小胶质细胞中表达的AD的强遗传风险因子）之间的关键联系，并表明这种相互作用通过调节小胶质细胞反应促进AD的致病事件。本文的在线版本（10.1186/s13024-018-0247-7）包含补充材料，可供授权用户使用。
TREM2 is an innate immune receptor specifically expressed in microglia. Coding variations in TREM2 have been reported to increase the risk for Alzheimer’s disease (AD) and other neurodegenerative diseases. While multiple studies support a role for TREM2 in microglial recruitment to amyloid plaques, the chemoattractant factor modulating TREM2-dependent microglial responses has not been defined. Potential binding of oligomeric amyloid-β 1–42 (oAβ1–42) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oAβ1–42 to activate TREM2 signaling pathways was examined by analyzing the phosphorylation of Syk and Akt in primary microglia as well as TREM2-mediated signaling in a reporter cell system. Lastly, the functional outcome of oAβ1–42-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oAβ1–42-bearing brain areas in vivo. We found that oAβ1–42 bound to TREM2 with high affinity and activated TREM2-dependent signaling pathway. Neither monomeric nor scrambled Aβ bound to TREM2 supporting a specific interaction between oAβ and TREM2. The disease-associated mutations of TREM2 reduced its binding affinity to oAβ1–42. Furthermore, we identified several positively charged amino acids within residues 31–91 of TREM2 that were crucial for its interaction with oAβ1–42. Importantly, oAβ1–42 promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner. Our data establish a critical link between oAβ1–42, a major pathological component of AD, and TREM2, a strong genetic risk factor for AD expressed in microglia, and suggest that such interaction contributes to the pathogenic events in AD by modulating microglial responses. The online version of this article (10.1186/s13024-018-0247-7) contains supplementary material, which is available to authorized users.
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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
DOI：
10.1084/jem.20142322
发表时间：
2015-03-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jay TR;Miller CM;Cheng PJ;Graham LC;Bemiller S;Broihier ML;Xu G;Margevicius D;Karlo JC;Sousa GL;Cotleur AC;Butovsky O;Bekris L;Staugaitis SM;Leverenz JB;Pimplikar SW;Landreth GE;Howell GR;Ransohoff RM;Lamb BT
通讯作者：
Lamb BT
影响因子：
4.4
作者：
Hamerman, Jessica A.;Jarjoura, Vessica R.;Lanier, Lewis L.
通讯作者：
Lanier, Lewis L.
影响因子：
4.4
作者：
Daws, MR;Sullam, PM;Seaman, WE
通讯作者：
Seaman, WE
影响因子：
3.3
作者：
Lee, C. Y. Daniel;Landreth, Gary E.
通讯作者：
Landreth, Gary E.