Proteomic Study on the Amelioration of Cognitive Impairments in 3×Tg-AD Mice by Treadmill Exercise

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Exercise can delay the onset of AD and improve cognitive dysfunction, but its underlying mechanism still needs further exploration. In this study, 6-month-old transgenic mice underwent a 12-week treadmill exercise intervention. The water maze experiment demonstrated that the learning and memory abilities of AD-exercise (ADE) mice were significantly superior to those of the wild-type mice. The proteomics analysis identified several proteins that were significantly upregulated or downregulated after treadmill exercise, such as SYT1, SLC25A5, and DLST in the hippocampal tissue; OPA1, NSF, DLG2, and DNM1 in the cortical tissue; and APP, APOE, MAP2, MAPT, SYP, SYN1/2, and DYNC1H1 in the cerebellar tissue. The functional enrichment analysis suggested that mitochondrial dysfunction, synaptic vesicle transport, and amyloid fibril formation in AD mice tend to recover to levels similar to those of wild-type mice. At the same time, the processes of exercise-induced axon guidance, protein stabilization, and negative regulation of apoptosis were enhanced more effectively than in wild-type animals. These results will help us understand how exercise improves cognition in AD mice.