Treadmill exercise decreases amyloid-beta burden possibly via activation of SIRT-1 signaling in a mouse model of Alzheimer's disease

Abstract

Accumulation of amyloid-beta (A beta) correlates significantly with progressive cognitive deficits, a main symptom of Alzheimer's disease (AD). Although treadmill exercise reduces A beta levels, the molecular mechanisms underlying the effects are not fully understood. We hypothesize that treadmill exercise decreases All production and alleviates cognitive deficits by activating the non-amyloidogenic pathway via SIRT-1 signaling. Treadmill exercise improved cognitive deficits and alleviated neurotoxicity. Most importantly, treadmill exercise increased SIRT-1 level, which subsequently resulted in increased ADAM-10 level by down-regulation of ROCK-1 and upregulation of RAR beta, ultimately facilitating the non-amyloidogenic pathway. Treadmill exercise-induced activation in SIRT-1 level also elevated PGC-1 alpha level and reduced BACE-1 and C-99 level, resulting in inhibition of the amyloidogenic pathway. Treadmill exercise may thus inhibit Ala production via upregulation of SIRT-1, which biases amyloid precursor protein processing toward the non-amyloidogenic pathway. This study provides novel and valuable insight into the molecular mechanisms possibly by which treadmill exercise reduces A beta production. (C) 2016 Elsevier Inc. All rights reserved.