Treadmill exercise inhibits amyloid-β generation in the hippocampus of APP/PS1 transgenic mice by reducing cholesterol-mediated lipid raft formation

The deposition of amyloid-beta (A beta) is one of the major pathological hallmarks of Alzheimer's disease (AD), and a higher cholesterol level is involved in the deposition of A beta. Previous evidence suggested that exercise exerts neuroprotective effects in a variety of AD models. In the present study, we investigated the effects of a 12-week treadmill exercise program on A beta deposits in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and the potential underlying mechanism. After 12 weeks of exercise, A beta deposits were significantly decreased in the hippocampus. Meanwhile, the amyloidogenic pathway of APP metabolism was inhibited, which was associated with a decrease in BACE1 expression. The APP metabolism mediated by the nonamyloidogenic pathway, as indicated by the increase in ADAM10 levels. Coincidentally, exercise reduced the cholesterol level, as evidenced by a significant decrease in the total cholesterol level and the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, as well as a reduction in the number of lipid rafts, as evidenced by a significant decrease in the flotillin 1 level. These finding suggested that the 12-week treadmill exercise program reduced A beta deposition in the hippocampus of APP/PS1 mice, possibly by regulating ADAM10 and BACE1 levels and by decreasing cholesterol-mediated lipid raft formation, indicating that exercise represents a therapeutic intervention to treat AD.