Physical exercise as a preventive and therapeutic strategy against behavioral dysfunction in Alzheimer's disease

Abstract

Physical exercise has been associated with neuronal protection against age-related alterations and is recommended as a preventive and therapeutic non-pharmacological strategy in the management of patients with neurodegenerative disorders, including Alzheimer's disease (AD). Due to their central role in several biological cell mechanisms and their role as key players against several pathological constrains, it is known that mitochondria may have an important association with the cross-tolerance phenomena between exercise and AD, particularly. In order to contribute to establish the state of the art and increase the scientific knowledge in this issue, the present dissertation comprises one literature review and one animal-based experimental study that were developed using an already established sporadic model of AD, the most prevalent and representative form of the disease, in opposition to the so called familiar. Herein, we intended to analyze the effects of chronic exercise, used as both preventive (before disease induction) and therapeutic (throughout and after the presence of the disease) strategies on brain cortex and hippocampus mitochondrial structural and functional alterations in a sporadic AD-like model. We also intended to evaluate, whether a chronic-endurance training program combined with an active lifestyle (mimicked here by the free access to wheel running) could delay or even prevent AD behavioral phenotyping progression. Therefore, we used in vitro mitochondrial oxygen consumption endpoints, histophotometric analysis from electron microscopy, and behavioral analysis to address our question. Our data suggest that chronic exercise improved spatial learning and memory deficits and mitigated deleterious morphological alterations characterizing AD, including diminished synapse number, severe damage scores, and injured mitochondria. Positive alterations were observed in mitochondrial oxygen consumption endpoints, including state 3, state 4, and respiratory control ratio (either using complex I or II-driven substrates) in synaptosomal and non-synaptosomal mitochondria. Moreover, our data also suggest that voluntary physical activity per se was not able to counteract the deleterious AD effects, although when accompanied by chronic endurance treadmill running (either lifelong or later-life) may be able to prevent or reverse cognitive and phenotypic impairments associated with AD. Ultimately, these findings will contribute to better understand the effects of different exercise types and timings throughout life span in the progression of the disease in this specific model, reinforcing the key role of mitochondrial adaptations in this process.