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

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.

Automated summary

This study reveals that TREM2 attenuates the activation of classical complement cascade by binding to its initiator C1q, providing mechanistic insights into the protective roles of TREM2 against AD pathogenesis. The formation of TREM2-C1q complexes in the human AD brains is associated with lower C3 deposition but higher amounts of synaptic proteins. Trem2 haploinsufficiency in mice increases complement-mediated microglial engulfment of synapses and accelerates synaptic loss, while administration of a TREM2 peptide rescues synaptic impairments in AD mouse models.