Physical exercise improves synaptic dysfunction and recovers the loss of survival factors in 3xTg-AD mouse brain

• 3xTg-AD mice showed dysfunction of GABAA and NMDA binding.
• 3xTg-AD mice showed lower levels of synaptic and pro-survival proteins.
• Exercise therapy improved GABAA and NMDA receptor functionalities.
• Exercise therapy protected against the loss of pre- and postsynaptic proteins.
• SIRT1 and GDNF may be involved in key mechanisms of exercise benefices.

Physical exercise has become a potentially beneficial therapy for reducing neurodegeneration symptoms in Alzheimer's disease. Previous studies have shown that cognitive deterioration, anxiety and the startle response observed in 7-month-old 3xTg-AD mice were ameliorated after 6 months of free access to a running wheel. Also, alterations in synaptic response to paired-pulse stimulation were improved. The present study further investigated some molecular mechanisms underlying the beneficial effects of 6 months of voluntary exercise on synaptic plasticity in 7-month-old 3xTg-AD mice. Changes in binding parameters of [3H]-flunitrazepam to GABAA receptor and of [3H]-MK-801 to NMDA receptor in cerebral cortex of 3xTgAD mice were restored by voluntary exercise. In addition, reduced expression levels of NMDA receptor NR2B subunit were reestablished. The synaptic proteins synaptophysin and PSD-95 and the neuroprotective proteins GDNF and SIRT1 were downregulated in 3xTgAD mice and were recovered by exercise treatment. Overall, in this paper we highlight the fact that different interrelated mechanisms are involved in the beneficial effects of exercise on synaptic plasticity alterations in the 3xTg-AD mouse model.