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

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. © 2014 Elsevier Ltd. All rights reserved.This study was supported by grants SAF2009-13093-C02-02, SAF2012-39852-C02-02 and CSD2010-00045 from the Spanish MINECO, 062931 from the Fundació La Marató de TV3, and the Catalan Generalitat (DURSI 2009/SGR/214); and the European Regional Development Fund (ERDF). Susana Revilla acknowledges supports from FPU, MCINN. Yoelvis García-Mesa acknowledges supports from the Fundació La Marató de TV3Peer Reviewe