Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, 361102, China.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Mol Neurodegener. 2018 Mar 27;13(1):15. doi: 10.1186/s13024-018-0247-7.
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 (oAβ) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oAβ 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 oAβ-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oAβ-bearing brain areas in vivo.
We found that oAβ 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 oAβ. Furthermore, we identified several positively charged amino acids within residues 31-91 of TREM2 that were crucial for its interaction with oAβ. Importantly, oAβ promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner.
Our data establish a critical link between oAβ, 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.
TREM2 是一种特异性表达于小胶质细胞的先天免疫受体。编码变异的 TREM2 已被报道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 TREM2 在小胶质细胞向淀粉样斑块募集中的作用，但调节 TREM2 依赖的小胶质细胞反应的趋化因子尚未确定。
通过固相结合、表面等离子体共振和免疫沉淀等互补方法检测寡聚体淀粉样β 1-42（oAβ）与 TREM2 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 TREM2 介导的报告细胞系统中的信号通路，研究 oAβ 激活 TREM2 信号通路的能力。最后，通过检测 oAβ 对体外小胶质细胞迁移和体内 oAβ 携带脑区小胶质细胞聚集的影响，测试 oAβ-TREM2 相互作用的功能结果。
我们发现 oAβ 与 TREM2 具有高亲和力结合并激活 TREM2 依赖的信号通路。单体或 scrambled Aβ 均不与 TREM2 结合，支持 oAβ 与 TREM2 之间的特异性相互作用。TREM2 的疾病相关突变降低了其与 oAβ 的结合亲和力。此外，我们确定了 TREM2 中 31-91 位残基内的几个正电荷氨基酸对于其与 oAβ 的相互作用至关重要。重要的是，oAβ 以 TREM2 依赖的方式促进体外小胶质细胞迁移和体内聚集。
我们的数据在 AD 的主要病理成分 oAβ 和在小胶质细胞中表达的 AD 的强遗传风险因素 TREM2 之间建立了一个关键联系，并表明这种相互作用通过调节小胶质细胞反应为 AD 的发病机制事件做出贡献。
