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 language | English (US) |
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Pages (from-to) | 10984-10997 |
Number of pages | 14 |
Journal | FASEB Journal |
Volume | 34 |
Issue number | 8 |
DOIs | |
State | Published - Aug 1 2020 |
Keywords
- Alzheimer's disease
- FAK/Rac1/Cdc42 pathway
- TREM2
- microglia
- migration
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics