The accumulation of amyloid-ß (Aß) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Aß by the proteolytic processing of amyloid precursor protein (APP) through the endocytic pathway, whereas microglia mediate Aß 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 Aß42 oligomers to ß1-integrin triggers the cofilin activation, and in turn, cofilin promotes the internalization of surface ß1-integrin. However, a role for cofilin in APP processing and Aß 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 Aß production by increasing surface APP (sAPP) levels. Expression of active (S3A) but not inactive (S3E) cofilin reduces sAPP levels by enhancing APP endocytosis. Accordingly, Aß deposition in APP and presenilin 1 (PS1) transgenic mice is significantly reduced by genetic reduction of cofilin (APP/PS1;cofilin+/-). However, the reduction of Aß load in APP/PS1;cofilin+/- mice is paradoxically associated with significantly increased ionized calcium-binding adaptor molecule 1-positive microglial activation surrounding Aß deposits. Primary microglia isolated from cofilin+/- mice demonstrate significantly enhanced state of activation and greater ability to uptake and clear Aß42, 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 Aß accumulation via dual and opposing endocytic mechanisms of promoting Aß production in neurons and inhibiting Aß 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-ß clearance.