Exercise upregulates Mitsugumin 53 and ameliorates behavioral deficits and mitochondrial biogenesis in a sporadic Alzheimer's disease model in rats.

Abstract

Chronic physical exercise is a promising non-pharmacological strategy to mitigate the progression of Alzheimer's disease (AD), yet the underlying molecular mechanisms remain incompletely understood. This study investigated the effects of chronic treadmill exercise on behavioral deficits and key molecular pathways in a d-galactose and AlCl-induced rat model of sporadic AD. Animals were assigned to control, AD, exercise and AD + exercise (AE) groups for a ten-week intervention. Behavioral assessments included the elevated plus maze and Morris Water Maze, followed by molecular and biochemical analyses (RT-qPCR, ELISA) of the hippocampus, skeletal muscle, and plasma. Our results demonstrate that the AD model induced profound cognitive impairments, diminished locomotor activity, heightened anxiety-like behavior, and elevated plasma tau levels. These pathological changes were accompanied by a significant downregulation of the AMPK/SIRT1/PGC-1α mitochondrial biogenesis pathway and, notably, a marked suppression of the membrane repair protein Mitsugumin 53 (MG53) in both the hippocampus and skeletal muscle. The physical exercise regimen successfully ameliorated these behavioral deficits and normalized plasma tau. Mechanistically, physical exercise potently upregulated the AMPK/PGC-1α/FNDC5/BDNF axis in both central and peripheral tissues. Crucially, this study reveals for the first time that physical exercise also triggers a robust upregulation of MG53 at both the gene and protein levels in the brain, muscle, and circulation. These findings identify the physical exercise-induced mobilization of MG53 as a novel and powerful neuroprotective mechanism, linking systemic cellular repair capacity to the enhancement of cognitive resilience against AD.