Regular and moderate exercise initiated in middle age prevents age-related amyloidogenesis and preserves synaptic and neuroprotective signaling in mouse brain cortex.

Although the beneficial responses induced in the central nervous system by early-initiated exercise have been broadly investigated, the effects of a chronic and moderate lately-initiated exercise on biochemical hallmarks of very early brain senescence have not been extensively studied. We previously reported that a midlife-initiated regimen of moderate running was able not only to prevent the age-related decay of antioxidative and detoxification functions in mouse brain cortex, but also to preserve neurotrophic support and molecular integrity. On this basis, this work investigated whether and how a 2-mo or 4-mo midlife-initiated running protocol could affect the activity of those systems involved in maintaining neuronal function and in preventing the onset of neurodegeneration within the brain cortex of middle-aged CD-1 mice. In particular, we analyzed the production of the peptide amyloid-β and the expression of synapsin Ia, which is known to play a key role in neurotransmission and synaptic plasticity. In addition, we studied the expression of sirtuin 3, as a protein marker of neuroprotection against age-dependent mitochondrial dysfunction, as well as the pro-death pathway induced by proBDNF through the interaction with p75NTR and the co-receptor sortilin. The midlife-initiated 4-mo running program triggered multiple responses within the mouse brain cortex, through the activation of anti-amyloidogenic, pro-survival, synaptogenic and neuroprotective pathways. However, most of the beneficial actions of the exercise regimen appeared only after 4months, since 2-mo-exercised mice showed marked impairments of the endpoints we considered. This could imply that a midlife-initiated regimen of moderate treadmill running may require an adequate time lag to activate beneficial compensative mechanisms within the mouse brain cortex.