Citations 2
Activation of FAK/Rac1/Cdc42‐GTPase signaling ameliorates impaired microglial migration response to Aβ 42 in triggering receptor expressed on myeloid cells 2 loss‐of‐function murine models
Rong, Zhouyi , Cheng, Baoying, Zhong, Li , Jia, Lin , Li, Yanfang , Shue, Francis , Wang, Na , Cheng, Yiyun , Huang, Xiaohua , Liu, Chia‐Chen , Fryer, John Denis , Wang, Xin , Zhang, Yun‐wu , Zheng, Honghua , Liu, Chia-Chen , Shue, Francis , Ye, Xiaowen , Li, Xin , Wang, Na
The FASEB Journal | July 29, 2020 | Volume: 34 | Issue: 8 | Pages: 10984-10997
Abstract Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid‐β (Aβ) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2‐regulated microglia recruitment to Aβ plaques remains unresolved. Here, we confirm that TREM2 mutation attenuates microglial migration. Then, using Trem2 −/− mice and an R47H variant mouse model for AD generated for this study, we show that TREM2 deficiency or the AD‐associated R47H mutation results in inhibition of FAK and Rac1/Cdc42‐GTPase signaling critical for cell migration. Intriguingly, treatment with CN04, a Rac1/Cdc42‐GTPase activator, partially enhances microglial migration in response to oligomeric Aβ 42 in Trem2 −/− or R47H microglia both in vitro and in vivo. Our study shows that the dysfunction of microglial migration in the AD‐associated TREM2 R47H variant is caused by FAK/Rac1/Cdc42 signaling disruption, and that activation of this signaling ameliorates impaired microglial migration response to Aβ 42 , suggesting a therapeutic target for R47H‐bearing patients with high risk of AD.
Soluble TREM2 induces inflammatory responses and enhances microglial survival
Zhong, Li , Chen, Xiao‐Fen , Liao, Chunyan , Huang, Ruizhi, Wang, Daxin , Wu, Linbei, Jia, Lin , Zheng, Honghua , Painter, Meghan M. , Atagi, Yuka, Liu, Chia‐Chen , Zhang, Yun‐wu , Fryer, John Denis , Xu, Huaxi , Bu, Guojun , Painter, Meghan , Atagi, Yuka , Liu, Chia-Chen , Fryer, John D., Wang, Tingting , Wang, Zhe , Wang, Zongqi , Li, Xinxiu , Bu, Guojun
Journal of Experimental Medicine | February 16, 2017 | Volume: 214 | Issue: 3 | Pages: 597-607
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and Trem2-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.