小柯机器人

厦门大学陈小芬等研究人员合作发现，TREM2受体在神经退行性变过程中通过与补体C1q结合防止补体介导的突触丢失。该研究于2023年7月12日在线发表于国际一流学术期刊《免疫》。

研究人员发现髓系细胞上表达的触发受体2（TREM2）通过与其启动子C1q的高亲和性结合，特异性地减弱了经典补体级联的激活。在人类阿尔茨海默病（AD）大脑中，检测到TREM2-C1q复合物的形成，并且复合物密度的增加与C3沉积的降低和突触蛋白数量的增加有关。在表达突变型人源tau的小鼠中，Trem2单倍体缺陷增加了补体介导的小胶质细胞吞噬突触和加速突触丢失。

研究人员发现TREM2与C1q结合的41个氨基酸TREM2多肽能挽救AD小鼠模型的突触损伤。因此，研究人员证明了小胶质细胞TREM2在神经变性过程中限制补体介导突触消除中的关键作用，为TREM2在AD发病机制中的保护作用提供了机理上的见解。

据悉，TREM2与AD风险密切相关，但其功能尚不完全清楚。

附：英文原文

Title: TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration

Author: Li Zhong, Xuan Sheng, Wanbing Wang, Yanzhong Li, Rengong Zhuo, Kai Wang, Lianshuai Zhang, Dan-Dan Hu, Yujuan Hong, Linting Chen, Hengjun Rao, Tingting Li, Muyang Chen, Zhihao Lin, Yun-wu Zhang, Xin Wang, Xiao-Xin Yan, Xiaochun Chen, Guojun Bu, Xiao-Fen Chen

Issue&Volume: 2023-07-12

Abstract: Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer’sdisease (AD) risk, but its functions are not fully understood. Here, we found thatTREM2 specifically attenuated the activation of classical complement cascade via high-affinitybinding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexeswas detected, and the increased density of the complexes was associated with lowerdeposition of C3 but higher amounts of synaptic proteins. In mice expressing mutanthuman tau, Trem2 haploinsufficiency increased complement-mediated microglial engulfment of synapsesand accelerated synaptic loss. Administration of a 41-amino-acid TREM2 peptide, whichwe identified to be responsible for TREM2 binding to C1q, rescued synaptic impairmentsin AD mouse models. We thus demonstrate a critical role for microglial TREM2 in restrictingcomplement-mediated synaptic elimination during neurodegeneration, providing mechanisticinsights into the protective roles of TREM2 against AD pathogenesis.

DOI: 10.1016/j.immuni.2023.06.016

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00273-X

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