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

• Published in: Immunity (Cambridge, Mass.) Vol. 56; no. 8; pp. 1794 - 1808.e8
• Main Authors: Zhong, Li, Sheng, Xuan, Wang, Wanbing, Li, Yanzhong, Zhuo, Rengong, Wang, Kai, Zhang, Lianshuai, Hu, Dan-Dan, Hong, Yujuan, Chen, Linting, Rao, Hengjun, Li, Tingting, Chen, Muyang, Lin, Zhihao, Zhang, Yun-wu, Wang, Xin, Yan, Xiao-Xin, Chen, Xiaochun, Bu, Guojun, Chen, Xiao-Fen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.08.2023
• Subjects: Alzheimer Disease - complications; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer’s disease; Animals; Brain - metabolism; C1q; complement; Complement Activation; Complement C1q - genetics; Complement C1q - metabolism; Humans; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; microglia; Microglia - metabolism; neurodegeneration; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Synapses - metabolism; synaptic loss; TREM2; C3; C1q; Alzheimer’s disease; synaptic loss; neurodegeneration; TREM2; complement; microglia
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2023.06.016

Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer’s disease (AD) risk, but its functions are not fully understood. Here, we found that TREM2 specifically attenuated the activation of classical complement cascade via high-affinity binding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexes was detected, and the increased density of the complexes was associated with lower deposition of C3 but higher amounts of synaptic proteins. In mice expressing mutant human tau, Trem2 haploinsufficiency increased complement-mediated microglial engulfment of synapses and accelerated synaptic loss. Administration of a 41-amino-acid TREM2 peptide, which we identified to be responsible for TREM2 binding to C1q, rescued synaptic impairments in AD mouse models. We thus demonstrate a critical role for microglial TREM2 in restricting complement-mediated synaptic elimination during neurodegeneration, providing mechanistic insights into the protective roles of TREM2 against AD pathogenesis. [Display omitted] •TREM2 interacts with C1q in vitro and in vivo•TREM2 suppresses the classical complement cascade by binding to C1q•Trem2 insufficiency increases complement-mediated synaptic loss in AD mice models•A TREM2 peptide that binds to C1q rescues synaptic impairments in AD mouse models TREM2 is strongly linked to Alzheimer’s disease risk, but its functions are not fully understood. Zhong et al. discovered that TREM2 suppresses complement activity and synaptic loss by binding to C1q. They identified a 41-amino-acid TREM2 peptide that restricts complement-mediated synaptic elimination during neurodegeneration.