| First Author | Liu T | Year | 2019 |
| Journal | FASEB J | Volume | 33 |
| Issue | 12 | Pages | 14234-14247 |
| PubMed ID | 31646885 | Mgi Jnum | J:297597 |
| Mgi Id | MGI:6472475 | Doi | 10.1096/fj.201901268R |
| Citation | Liu T, et al. (2019) Dual role of cofilin in APP trafficking and amyloid-beta clearance. FASEB J 33(12):14234-14247 |
| abstractText | The accumulation of amyloid-beta (Abeta) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Abeta by the proteolytic processing of amyloid precursor protein (APP) through the endocytic pathway, whereas microglia mediate Abeta clearance also via endocytic mechanisms. Previous studies have shown the critical importance of cofilin, a filamentous actin-severing protein, in actin dynamics and pathogen-triggered endocytic processes. Moreover, the binding of Abeta42 oligomers to beta1-integrin triggers the cofilin activation, and in turn, cofilin promotes the internalization of surface beta1-integrin. However, a role for cofilin in APP processing and Abeta metabolism has not been investigated. In this study, we found that knockdown of cofilin in Chinese hamster ovary 7WD10 cells and primary neurons significantly reduces Abeta production by increasing surface APP (sAPP) levels. Expression of active (S3A) but not inactive (S3E) cofilin reduces sAPP levels by enhancing APP endocytosis. Accordingly, Abeta deposition in APP and presenilin 1 (PS1) transgenic mice is significantly reduced by genetic reduction of cofilin (APP/PS1;cofilin(+/-)). However, the reduction of Abeta load in APP/PS1;cofilin(+/-) mice is paradoxically associated with significantly increased ionized calcium-binding adaptor molecule 1-positive microglial activation surrounding Abeta deposits. Primary microglia isolated from cofilin(+/-) mice demonstrate significantly enhanced state of activation and greater ability to uptake and clear Abeta42, which is reversed with the active (S3A) but not inactive (S3E) form of cofilin. These results taken together indicate a significant role for cofilin in Abeta accumulation via dual and opposing endocytic mechanisms of promoting Abeta production in neurons and inhibiting Abeta clearance in microglia.-Liu, T., Woo, J.-A. A., Yan, Y., LePochat, P., Bukhari, M. Z., Kang, D. E. Dual role of cofilin in APP trafficking and amyloid-beta clearance. |
