TY - JOUR
T1 - TREM2 promotes microglial survival by activating wnt/β-catenin pathway
AU - Zheng, Honghua
AU - Jia, Lin
AU - Liu, Chia Chen
AU - Rong, Zhouyi
AU - Zhong, Li
AU - Yang, Longyu
AU - Chen, Xiao Fen
AU - Fryer, John D.
AU - Wang, Xin
AU - Zhang, Yun Wu
AU - Xu, Huaxi
AU - Bu, Guojun
N1 - Publisher Copyright:
© 2017 the authors.
PY - 2017/2/15
Y1 - 2017/2/15
N2 - 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.
AB - 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.
KW - Akt/GSK3β signaling pathway
KW - Alzheimer’s disease
KW - Cell survival
KW - Microglia
KW - TREM2
KW - Wnt/β-catenin signaling pathway
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U2 - 10.1523/JNEUROSCI.2459-16.2017
DO - 10.1523/JNEUROSCI.2459-16.2017
M3 - Article
C2 - 28077724
AN - SCOPUS:85013127196
SN - 0270-6474
VL - 37
SP - 1772
EP - 1784
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 7
ER -