Extracellular vesicle-associated irisin mediates the beneficial effects of exercise in Alzheimer's disease
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Authors
Hunter, Tai Raina
Date
2025-05-29
Type
thesis
Language
eng
Keyword
Alzheimer's disease , Extracellular vesicles , Exercise
Alternative Title
Abstract
Alzheimer’s disease (AD) is a multifactorial, progressive neurodegenerative disease and the leading cause of dementia in older adults. No effective therapeutics are currently available, but lifestyle factors may influence up to 40% of AD risk. Physical exercise is one of the most powerful behavioural interventions known to maintain cognitive health as we age and to delay AD onset. Among the molecular mediators of the neuroprotective functions of exercise is irisin, an exerkine cleaved from the transmembrane protein fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin is capable of inducing brain derived neurotrophic factor (BDNF) and restoring memory function in AD models. However, little is known about the mechanisms that mediate this periphery-brain crosstalk. Emerging evidence suggests that extracellular vesicles (EVs) released into circulation during physical exercise may serve as vehicles for FNDC5/irisin transport. Here, we hypothesized that exercise enriches EVs with FNDC5/irisin to mediate the beneficial effects of exercise on memory in AD. We show that EVs containing FNDC5/irisin as luminal cargo can be effectively isolated from human plasma with two methods, size exclusion chromatography and polymer-based precipitation. In adult males, six weeks of high-intensity interval training upregulates FNDC5/irisin in serum EVs, which positively correlates with serum BDNF. In mice, chronic swimming exercise, but not chronic voluntary running, enriches circulating EVs with FNDC5/irisin. Importantly, intravenous treatment with EVs obtained from exercised wild-type mice, but not from exercised FNDC5 knockout mice, elevates the expression of BDNF in the frontal cortex and rescues memory in an AD mouse model. Finally, we observed reduced levels of both EV-FNDC5/irisin and total EVs in a cohort of healthy older adults compared to younger individuals. Our identification of specific exerkines, and their transport mechanisms, that mediate the effects of exercise-induced neuroprotection in AD may form the basis of novel therapeutic strategies that mimic the effects of exercise. This has important implications for individuals with AD or age-related limitations that prevent regular physical activity, offering a potential strategy to pharmacologically attain the cognitive benefits of exercise. Lastly, our results suggest EV-FNDC5/irisin may also serve as a novel blood biomarker for age-related changes and brain resilience.