Treadmill exercise decreases β-amyloid burden in APP/PS1 transgenic mice involving regulation of the unfolded protein response

The accumulation of beta-amyloid protein (A beta) in the brain is one of major pathological hallmarks of Alzheimer's disease (AD). Overactivation of the unfolded protein response (UPR) signaling has been reported to lead to beta-amyloidogenesis. The current study aimed to investigate the effects of treadmill exercise on UPR signaling and the A beta production and to demonstrate whether exercise-induced AD reduction was associated with changes in UPR signaling. Three-month old male APP/PS1 transgenic and wild-type mice were subjected to treadmill exercise for 3 months. At the end of exercise (6 months old), the levels of A beta plaques and soluble forms of A beta, and proteins involve in the unfolded protein response (UPR) were analyzed in the hippocampus. Three months of treadmill exercise resulted in a robust reduction in A beta plaques and soluble forms of A beta in the hippocampus of APP/PS1 mice. This was accompanied by a significant decrease in beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and presenilin-1 (PS1) expression. Meanwhile, we found that treadmill exercise downregulated the expression of GRP78 and inhibited activation of PERK, eIF2 alpha, and ATF4, reflecting the involvement of the UPR signaling. Overall, our findings suggest that treadmill exercise may suppresse the overactivation of the UPR signaling as well as inhibit the amyloidogenic pathway in APP/PS1 mice, thus may serve as an useful approach for the prevention and treatment of AD.