TREM2 signalling as a multifaceted player in brain homoeostasis and a potential target for Alzheimer's disease treatment

Abstract

AbstractTriggering receptor expressed on myeloid cells‐2 (TREM2) has crucial roles in microglial physiology, differentiation, metabolism and survival. Genome‐wide association studies (GWAS) show that genetic mutations of the TREM2 increase the risk of late‐onset Alzheimer's disease (AD) by two to four times, disrupting the microglial function in reducing the progression of the disease. Accumulating data show that TREM2 function in AD is related primarily to the clearance of soluble and insoluble amyloid beta (Aβ42) aggregates from the brain. TREM2 also ameliorates the pathological effects of activated microglia on neuronal tau pathology, demonstrating its protective anti‐inflammatory effects. However, since the excessive activation of TREM2 signalling can inhibit pro‐inflammatory reactions and suppress the role of microglia in immune surveillance, at the late stages of the disease, it might promote immune tolerance, which is detrimental. The contradictory effects of TREM2 mutations on brain amyloidopathy and tauopathy in multiple mouse models, as well as studies revealing various effects of TREM2 overexpression, complicate the understanding of the role that TREM2 plays in AD aetiopathogenesis. In this review, we summarize the latest developments regarding the significance of TREM2 signalling in the stability of microglial pro‐ and anti‐inflammatory activations and propose the mechanisms that should be targeted in the future to treat AD.