Aerobic Exercise Preserves Capillary Oxygen Homeostasis and Neurovascular Function in a Mouse Model of Alzheimer's Disease

Abstract

Age-related cerebrovascular dysfunction is increasingly recognized as a critical contributor to cognitive decline and Alzheimers disease (AD) progression [1,2], yet the extent to which lifestyle interventions preserve microvascular oxygen delivery remains poorly defined. Physical activity (PA) improves vascular health and cognition in humans [3-7], but its impact on capillary-level oxygenation and functional hyperemia during aging and amyloid pathology is unknown. Here, we longitudinally quantified microvascular oxygen tension and stimulus-evoked oxygen dynamics in awake APP/PS1 mice and wild-type littermates using two-photon phosphorescence lifetime microscopy. Chronic 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 widespread capillary hypoxia and bimodal oxygen distributions, hallmarks of malignant microvascular dysfunction, which were largely absent in physically active animals. These findings demonstrate that routine aerobic PA preserves microvascular oxygen homeostasis and functional responsiveness during aging and amyloid accumulation, supporting a capillary-centric mechanism through which exercise confers neurovascular resilience in preclinical AD.