TREM2 protects against complement‐mediated synaptic loss via binding to C1q in neurodegeneration

Abstract

AbstractBackgroundThe triggering receptor expressed on myeloid cells 2 (TREM2) is recognized as the strongest immune‐specific genetic risk factor for Alzheimer’s disease (AD), since its heterozygous R47H variant confers a 3‐4‐fold increased risk of AD. It has been widely acknowledged that TREM2 plays versatile roles in regulating microglial functions by interacting with a variety of ligands.MethodWe performed affinity‐purification coupled to mass spectrometry with the TREM2‐Fc fusion construct to identify new binding partners for TREM2. The binding of TREM2 to new partners was further confirmed by a solid‐phase binding assay, surface plasmon resonance assay, dot blot binding assay and proximity ligation assay. Next, the functional effects of TREM2 binding to new partners were determined both in vitro and in vivo. We further performed serial truncations to determine the amino acid sequence in TREM2 responsible for binding to new partners. Finally, the functional effects of TREM2 peptide binding to new partners were examined in both the physiological and pathological contexts.ResultHere we show that C1q protein, the initiator of the classical complement pathway, is a binding partner for TREM2. TREM2 specifically attenuated the activation of classical complement cascade via high‐affinity binding to C1q in vitro. The formation of TREM2‐C1q complexes was also detected in human AD brain. Remarkably, the increased density of TREM2‐C1q complexes was associated with lower deposition of C3 but higher density of PSD95, pinpointing to a protective role of TREM2 against complement activity in AD brain. In mice expressing mutant human tau, Trem2 haploinsufficiency increased complement‐mediated microglial engulfment of synapses and accelerated synaptic loss with negligible effects on microglial density and tau pathology. We further identified a 41 amino acid sequence in TREM2 responsible for binding to C1q. In vivo administration of this short peptide reduced synapse removal by microglia and rescued synapse density in both the amyloidosis and tauopathy mouse models of AD.ConclusionTogether, our results demonstrate a critical role for microglial TREM2 in restricting complement‐mediated synaptic elimination in neurodegeneration, providing new mechanistic insights into the protective roles of TREM2 against AD pathogenesis.