The emerging neuroprotective roles of exerkines in Alzheimer's disease.

Despite the extensive knowledge of the beneficial effects of physical exercise, a sedentary lifestyle is still a predominant harm in our society. Sedentarism is one of the major modifiable risk factors for metabolic diseases such as diabetes mellitus, obesity and neurological disorders, including Alzheimer's disease (AD)-characterized by synaptic failure, amyloid protein deposition and memory loss. Physical exercise promotes neuroprotective effects through molecules released in circulation and mediates the physiological crosstalk between the periphery and the brain. This literature review summarizes the current understanding of the roles of exerkines, molecules released during physical exercise, as systemic and central factors that mediate the beneficial effects of physical exercise on cognition. We highlight the neuroprotective role of irisin-a myokine released from the proteolytic cleavage of fibronectin type III domain-containing protein 5 (FNDC5) transmembrane protein. Lastly, we review evidence pointing to physical exercise as a potential preventative and interventional strategy against cognitive decline in AD.

Interleukin-1ß mediates alterations in mitochondrial fusion/fission proteins and memory impairment induced by amyloid-ß oligomers.

BACKGROUND: The lack of effective treatments for Alzheimer's disease (AD) reflects an incomplete understanding of disease mechanisms. Alterations in proteins involved in mitochondrial dynamics, an essential process for mitochondrial integrity and function, have been reported in AD brains. Impaired mitochondrial dynamics causes mitochondrial dysfunction and has been associated with cognitive impairment in AD. Here, we investigated a possible link between pro-inflammatory interleukin-1 (IL-1), mitochondrial dysfunction, and cognitive impairment in AD models. METHODS: We exposed primary hippocampal cell cultures to amyloid-ß oligomers (AßOs) and carried out AßO infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of AßOs on proteins that regulate mitochondrial dynamics. Where indicated, primary cultures were pre-treated with mitochondrial division inhibitor 1 (mdivi-1), or with anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist used in the treatment of rheumatoid arthritis. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of AßOs in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1ß) in AßO-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1-/-) mice received an i.c.v. infusion of AßOs. RESULTS: We report that anakinra prevented AßO-induced alteration in mitochondrial dynamics proteins in primary hippocampal cultures. Altered levels of proteins involved in mitochondrial fusion and fission were observed in the brains of cynomolgus macaques that received i.c.v. infusions of AßOs. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by AßOs in mice. In addition, AßOs failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1-/- mice. CONCLUSION: These findings indicate that IL-1ß mediates the impact of AßOs on proteins involved in mitochondrial dynamics and that strategies aimed to prevent pathological alterations in those proteins may counteract synapse loss and cognitive impairment in AD.