Dissecting The Roles Of TREM2-Clq Interaction In Synaptic Homeostasis Of Adult Mice Brain

Triggering receptor expressed on myeloid cells 2(TREM2)is a microglial innate immune receptor genetically linked to a series of neurodegenerative diseases,including Alzheimer's disease(AD)and Nasu-Hakola disease(NHD).Complement component lq(C1q)is a protein complex involved in the innate immune system to defense against infection in the peripheral circulation and regulates microglia-mediated synapse pruning in the brain.Here,we show that TREM2 binds directly to C1q and find the NHD-associated mutations of TREM2 increase its binding affinity to C1q while the AD-related variants have a minimal effect on the binding affinity.The absence of Trem2 resulted in synapse loss,accompanied by increased microglial phagocytosis of synapse after Clq injected into the adult brain.Similarly,Clq enhanced synaptosome engulfment in the primary microglia of Trem2-deficient(Trem2-/-)mice.Furthermore,a JNK inhibitor SP600125 blocks C1y-induced phagocytosis of synaptosome in Trem2-/-microglia.Overall,our study firstly links the TREM2-Clq interaction to the protective role of TREM2 in Clq-mediated synapse loss in the adult brain,which may provide insights into the molecular mechanism that underlie long-term dendrite stabilization in the healthy adult brain.