Aim: 

Physical exercise improves general health and reduces frailty in non-demented elderly people. Cognitive improvement was reported in people at risk of Alzheimer's disease (AD) after a short exercise program. We have initiated a study in a triple transgenic mouse model of AD (3xTgAD) to analyze the timing-related effects of exercise on cognitive loss and the underlying neuroprotective mechanisms.

Methods: 

Male and female 3xTgAD and wild type mice have free access to an activity wheel. Mice are submitted to one month of exercise at different ages: shortly after weaning, at early symptomatic ages and at older ages with overt AD signs. Then, sensorimotor, BPSD-like behaviours and learning and memory are tested. Brain amyloid beta is determined by ELISA and immunohistochemistry. Levels of glutathione and antioxidant enzymes are quantified spectrophotometrically in cerebral cortex. Synaptic proteins, neurotrophins, pCREB and NMDAR2B are determined in hippocampus by Western blotting.

Results: 

We have analyzed the effects of voluntary exercise at early AD phases (4 and 7 months old mice) whereas late phases (12-18 months) are ongoing. Main behavioural alterations at early phases were higher anxiety and slight cognitive loss. In general, exercise ameliorated neuropathological behaviours, but did not decrease amyloid beta in brain. Main significant changes after exercise were an increase of antioxidant defences and a tendency to restore levels of GDNF and NMDAR2B.

Conclusion: 

The neuroprotective mechanisms are not yet clarified, but physical exercise may be a promising coadyuvant therapy to prevent or ameliorate aging-related cognitive decline either in non-demented and in AD patients.

This work was supported by grants 062931 from Fundació la Marató de TV3 and RD06/0913/1004 from Instituto de Salud Carlos III, Spain.