Chronic Aerobic Exercise Alleviates Amyloid-induced Capillary Dysfunction

Abstract Age-related cerebrovascular dysfunction is increasingly recognized as a critical contributor to cognitive decline and Alzheimer’s disease (AD) progression. Aerobic physical activity (PA) and other modifiable lifestyle interventions can substantially reduce the likelihood of dementia; however, their ability to mitigate cerebrovascular alterations remains poorly defined. PA reportedly improves systemic vascular health and cognitive function in aging humans, but its impact on cerebrovascular function during aging and amyloid β (Aβ) pathology is unclear. Here, we longitudinally quantified microvascular oxygen tension and stimulus-evoked oxygen dynamics in awake APP/PS1dE9 mice and wild-type littermates using two-photon phosphorescence lifetime microscopy. Routine aerobic PA initiated in early adulthood preserved basal arteriolar, capillary, and venular oxygenation, prevented age-dependent increases in microvascular heterogeneity, and mitigated excessive oxygen extraction in preclinical AD mice. While amyloid pathology impaired stimulus-evoked oxygen responses across vascular compartments, PA selectively enhanced capillary dilation and accelerated hyperemic kinetics without altering vascular density or architecture. Notably, sedentary AD mice developed lower, widely-dispersed distributions in capillary oxygenation, hallmarks of malignant microvascular dysfunction, which were largely absent in physically active animals. These findings demonstrate that routine aerobic PA preserves basal capillary oxygenation and stimulus-evoked hyperemia during aging and Aβ, supporting a capillary-centric mechanism through which exercise confers neurovascular resilience in preclinical AD. Competing Interest Statement The authors have declared no competing interest. Footnotes Additional analyses and figures have been added.