Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Aβ42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models

Zhouyi Rong, Baoying Cheng, Li Zhong, Xiaowen Ye, Xin Li, Lin Jia, Yanfang Li, Francis Shue, Na Wang, Yiyun Cheng, Xiaohua Huang, Chia-Chen Liu, John D. Fryer, Xin Wang, Yun wu Zhang, Honghua Zheng

Research output: Contribution to journalArticle

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 Aβ42 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 Aβ42, suggesting a therapeutic target for R47H-bearing patients with high risk of AD.

Original languageEnglish (US)
JournalFASEB Journal
DOIs
StateAccepted/In press - 2020

Keywords

  • Alzheimer's disease
  • FAK/Rac1/Cdc42 pathway
  • microglia
  • migration
  • TREM2

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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