The Effects And Mechanism Of TREM2 On Microglial Survival

Alzheimer's disease(AD)is a neurodegenerative disease andthe most common type of dementia.AD etiology is not clear and its pathogenesis is very complex involving multiple factors,such as age,environment,biology and genetics.ApoE has been recognized as a major risk gene for AD since a few decades ago.In recent years,Triggering Receptor Expressed on Myeloid cells 2(TREM2),which is mainly expressed in microglia,has been identified as an important AD risk gene.Microglia has been known to play an important role in the development of AD.Whether and how TREM2 may affect the functions of microglia is not clear,thus,it is of great significance to study the function of TREM2 in microglia for the understanding of the pathogenesis and exploration of the treatment of AD.To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia,we knocked down or knocked out Trem2 in vitro and in vivo models,respectively.We found that TREM2 deficiency reduced the viability and proliferation of primary microglia,inhibited microgliosis,and induced cell cycle arrest at G1/G0 phase,as wel as decreased the stability of ?-catenin,a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes including cell survival.TREM2 stabilized ?-catenin by inhibiting its degradation via the Akt/GSK3? signaling pathway.More importantly,treatment with Wnt3a or lithium chloride(LiCl),which activates the ?-catenin-mediated Wnt signaling pathway,rescued the detrimental phenotypes of reduced microglial viability and microgliosis in Trem2-/-microglia and in Trem2-/-mouse brain.Taken together,our studies demonstrate a critical role of TREM2-mediated Wnt/?-catenin pathway in microglial survival and suggest that therapeutically modulating this pathway may help to ameliorate impaired microglial survival and microgliosis associated with AD.