TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway

• DOI: 10.1523/jneurosci.2459-16.2017
• Publication Date: 2017-01-12T02:41:55Z
• Authors: Honghua Zheng; Lin Jia; Chia-Chen Liu; Zhouyi Rong; Li Zhong; Longyu Yang; Xiao-Fen Chen; John D. Fryer; Xin Wang; Yun-wu Zhang; Huaxi Xu; Guojun Bu
• Keywords: TREM2

Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed myeloid including microglia in the CNS, has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating or DAP12 lead to Nasu–Hakola disease; however, how AD risk-conferring variants increase not clear. To elucidate signaling pathways underlying reduced expression loss of function microglia, we respectively knocked down and out vitro vivo models. We found that deficiency viability proliferation primary microgliosis Trem2 −/− mouse brains, induced cell cycle arrest at G 1 /S checkpoint, decreased stability β-catenin, key component canonical Wnt pathway responsible maintaining many biological processes, survival. stabilized β-catenin by inhibiting degradation via Akt/GSK3β pathway. More importantly, treatment with Wnt3a, LiCl, TDZD-8, activates β-catenin-mediated pathway, rescued survival and/or brain. Together, our studies demonstrate critical role TREM2-mediated Wnt/β-catenin microglial suggest modulating this therapeutically may help combat impaired associated AD. SIGNIFICANCE STATEMENT Mutations (Triggering 2) gene are increased (AD) effective sizes comparable apolipoprotein E ( APOE ) ε4 allele, making it imperative understand molecular pathway(s) microglia. Our findings shed new light relationship between TREM2/DNAX-activating (DAP12) provide clues might impair pathogenesis. promotes activating possible restore when activity disrupted reduced. Therefore, potential manipulating TREM2/β-catenin