Neuron-derived Extracellular Vesicles in Blood Reveal Effects of Exercise in Alzheimer’s Disease

Abstract

Background Neuron-derived extracellular vesicles (NDEVs) in blood may be used to derive biomarkers for effects of exercise in Alzheimer’s disease (AD). For this purpose, we studied changes in neuroprotective proteins proBDNF, BDNF and humanin in plasma NDEVs from patients with mild to moderate AD participating in the randomized controlled trial (RCT) of exercise ADEX. Methods proBDNF, BDNF and humanin were quantified in NDEVs immunocaptured from the plasma of 95 ADEX participants, randomized into exercise and control groups, collected at baseline and 16-weeks. Exploratorily, we also quantified NDEV levels of putative exerkines known to respond to exercise in peripheral tissues. Results NDEV levels of proBDNF, BDNF and humanin increased in the exercise group, especially in APOE ε4 carriers, but remained unchanged in the control group. Inter-correlations between NDEV biomarkers observed at baseline were maintained after exercise. NDEV levels of putative exerkines remained unchanged. Conclusions Findings suggest that the cognitive benefits of exercise could be mediated by the upregulation of neuroprotective factors in NDEVs. Additionally, our results indicate that AD subjects carrying APOE ε4 are more responsive to the neuroprotective effects of physical activity. Unchanged NDEV levels of putative exerkines after physical activity imply that exercise engages different pathways in neurons and peripheral tissues. Future studies should aim to expand upon the effects of exercise duration, intensity, and type in NDEVs from patients with early AD and additional neurodegenerative disorders. Trial registration: The Effect of Physical Exercise in Alzheimer Patients (ADEX) was registered as ClinicalTrials.gov Identifier: NCT01681602 and was first submitted on April 30, 2012 and was first submitted that met QC criteria on September 5, 2012.