Triggering Receptor Expressed on Myeloid cells 2 (TREM2), expressed on myeloid cells including microglia in the central nervous system (CNS), has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its trans-membrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease (NHD); however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis in Trem2-/- mouse brains, induced cell cycle arrest at G1/S checkpoint, and decreased the stability of β-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes including cell survival. TREM2 stabilized β-catenin by inhibiting its degradation via the Akt/GSK3β signaling pathway. More important, treatment with Wnt3a, lithium chloride (LiCl) or TDZD-8, which activates the β-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis in Trem2-/- microglia and/or in Trem2-/- mouse brain. Taken together, our studies demonstrate a critical role of TREM2-mediated Wnt/β-catenin pathway in microglial viability and suggest that therapeutically modulating this pathway may help to combat impaired microglial survival and microgliosis associated with AD.
Mutations in the TREM2 gene are associated with increased risk for AD with effective sizes comparable to that of the apolipoprotein E (APOE) ε4 allele, making it imperative to understand the molecular pathway(s) underlying TREM2 function in microglia. Our findings shed new light on the relationship between TREM2/DAP12 signaling and Wnt/β-catenin signaling and provide clues as to how reduced TREM2 function might impair microglial survival in AD pathogenesis. We demonstrate that TREM2 promotes microglial survival by activating the Wnt/β-catenin signaling pathway and that it is possible to restore Wnt/β-catenin signaling when TREM2 activity is disrupted or reduced. As such, we demonstrate the potential of manipulating the TREM2/β-catenin signaling pathway for the treatment of AD.
↵* H.Z., L.J.and C.-C.L.are co-first authors.
The authors declare no competing financial interests.
This work was supported by a grant from the Natural Science Foundation of Fujian Province of China (No. 2016J01411 to H.Z.), a grant from the Educational Department of Fujian Province of China (No. JZ160403 to H.Z.) and NIH grants R01AG027924, R01AG035355, R01AG046205 (to G.B.), and grants (81100842 to H.Z., U1505227 to G.B., 81370459 and 31400914 to X.-F.C.) from the National Natural Science Foundation of China. This work was also supported by the Tanz Family Funds and Alzheimer's Association grant (C4C-15-369446) to Huaxi Xu.