| First Author | Rong Z | Year | 2020 |
| Journal | FASEB J | Volume | 34 |
| Issue | 8 | Pages | 10984-10997 |
| PubMed ID | 32613609 | Mgi Jnum | J:304182 |
| Mgi Id | MGI:6694390 | Doi | 10.1096/fj.202000550RR |
| Citation | Rong Z, et al. (2020) Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to Abeta42 in triggering receptor expressed on myeloid cells 2 loss-of-function murine models. FASEB J 34(8):10984-10997 |
| abstractText | Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid-beta (Abeta) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2-regulated microglia recruitment to Abeta 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 Abeta42 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 Abeta42 , suggesting a therapeutic target for R47H-bearing patients with high risk of AD. |
