TREM2 promotes microglial survival by activating wnt/β-catenin pathway

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 D Bu

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells 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 TREM2 or DAP12 lead to Nasu–Hakola disease; 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 the 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 importantly, treatment with Wnt3a, 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. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/β-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.

Original languageEnglish (US)
Pages (from-to)1772-1784
Number of pages13
JournalJournal of Neuroscience
Volume37
Issue number7
DOIs
StatePublished - Feb 15 2017

Keywords

  • Akt/GSK3β signaling pathway
  • Alzheimer’s disease
  • Cell survival
  • Microglia
  • TREM2
  • Wnt/β-catenin signaling pathway

ASJC Scopus subject areas

  • Neuroscience(all)

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    Zheng, H., Jia, L., Liu, C-C., Rong, Z., Zhong, L., Yang, L., Chen, X. F., Fryer, J. D., Wang, X., Zhang, Y. W., Xu, H., & Bu, G. D. (2017). TREM2 promotes microglial survival by activating wnt/β-catenin pathway. Journal of Neuroscience, 37(7), 1772-1784. https://doi.org/10.1523/JNEUROSCI.2459-16.2017