The benefits of physical exercise to reduce low-grade inflammation and improve Brain-Derived Neurotrophic Factor (BDNF) levels and cognitive function became a growing field of interest. Low-grade inflammation is common during aging and seems to be linked to neurodegenerative process. Regular physical exercises can help to reduce pro-inflammatory cytokines levels and to improve BDNF peripheral concentrations. The main goal of this research was to analyze the effects of a 16-week multimodal physical exercise program on peripheral BDNF levels and on Tumor Necrosis-α (TNF-α) and Interleukin- 6 (IL-6) as pro-inflammatory markers in cognitive healthy elderly individuals and in elderly with mild cognitive impairment (MCI). Cognitive functions were assessed by the Montreal Cognitive Assessment (MoCA) prior to and after the intervention. Thirty cognitively healthy participants and thirty-seven MCI participants were assigned to the control (CG) and trained (TG) groups. The TG participated in a multimodal physical training program for a 16-week period. The results showed a significant between-subjects interaction, which indicates the beneficial contribution of training on the reduction of TNF-α (p=0.001) and IL-6 (p<0.001) and on the improvement of BDNF (p<0.001) peripheral concentrations. Cognitive functions also presented significant improvements for MCI trained group (p=0.03). In conclusion, physical exercise was effective to reduce pro-inflammatory cytokines and to improve BDNF peripheral levels, with positive reflexes on cognition. To the best of our knowledge, this is the first study that evaluated longitudinally the effects of a multimodal physical exercises protocol on peripheral concentrations of pro-inflammatory cytokines and cognition performance in elderly MCI individuals.

The benefits of physical exercise on improvements in brain-derived neurotrophic factor (BDNF) levels and cognitive functioning have been reported in the literature. However, the variability of individual responses may be linked to genetic differences. BDNF is considered one of the most plausible factors involved in the cognitive benefits associated with physical activity practice. A single nucleotide polymorphism localized in the gene that codes BDNF results in a missense mutation that promotes an amino acid substitution (Val66Met) in the protein. This process has been associated with decreased levels of BDNF secretion, with corresponding impairments in specific cognitive functions. Therefore, the objective of this study was to analyze the effects of a multimodal physical exercise program on peripheral BDNF levels and cognitive functions in elderly individuals with mild cognitive impairment (MCI). The participants were genotyped for the BDNF Val66Met polymorphism. Cognitive functions were assessed by the Montreal Cognitive Assessment (MoCA) prior to and after the intervention. Forty-five participants were assigned to the control and trained groups. The trained group participated in a multimodal physical training for a 16-week period. The results showed a significant between-subjects interaction (p < 0.05), which indicates the beneficial contribution of training on cognitive functions independent of the BDNF genotype. However, only participants with BDNF-Met genotypes exhibited significant improvements in peripheral BDNF levels. The BDNF genotype appears to modulate the effects of physical exercise on BDNF secretion, but it does not influence cognition. This is the first study that evaluated the influence of a BDNF polymorphism on physical activity and cognition performance in elderly MCI individuals.

ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer’s disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective. As increased ADAM10 activity protects the brain from β-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review.