Neurovascular Restoration by Treadmill Exercise Attenuates Age-Related Cognitive Decline in Mice.

PURPOSE: Aging is associated with various physiological changes. These include microvascular dysfunction, which impairs cerebral blood flow and neuronal health, leading to cognitive impairment. Although exercise has demonstrated beneficial effects on aging, its specific impact on age-related microvascular dysfunction and blood-brain barrier (BBB) disruption requires further investigation. This study aimed to evaluate whether an 8-week treadmill exercise regimen in aged mice could improve cognitive impairment by alleviating microvascular and BBB damage and reducing neuroinflammation. METHODS: Twenty-month-old C57BL/6J male mice engaged in a treadmill exercise program for 60 minutes daily over 8 weeks. Cognitive function was assessed using the passive avoidance test. Microvascular integrity was evaluated by measuring microvessel length and fragmentation in the cortex using platelet endothelial cell adhesion molecule-1 as a marker. Activation of microglia and astrocytes was determined by analyzing the expression of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein through immunohistochemistry and immunofluorescence. BBB integrity was assessed by examining the expression levels of tight junction proteins, including zonula occludens-1, occludin, claudin-9, and platelet-derived growth factor receptor beta (PDGFRβ), in the cortex via immunostaining and western blotting. RESULTS: Treadmill exercise significantly improved cognitive function, as indicated by increased latency time in the passive avoidance test. Exercise intervention also increased microvessel length and decreased microvessel fragmentation in the cortex. Additionally, treadmill exercise reduced the activation of microglia and astrocytes, thereby decreasing neuroinflammatory responses. Furthermore, treadmill exercise preserved BBB integrity by maintaining the expression of tight junction proteins and PDGFRβ, counteracting age-related declines. CONCLUSION: The findings suggest that regular treadmill exercise mitigates cognitive impairment and vascular dysfunction associated with aging by improving microvascular health and BBB integrity. These results highlight the potential of exercise intervention as a non-pharmacological strategy for treating age-related neurodegenerative diseases by preserving vascular and BBB structures and reducing neuroinflammation.