Sex differences shape memory capacity declining during aging: rescue effects of voluntary exercise

Alzheimer’s Disease (AD) has higher incidence in women compared to men, but the biological bases of this increased vulnerability are still unknown. The aim of this study is to identify early markers of aging in female subjects to discover early disease’s mechanisms that make them more prone to develop dementia. Memory Capacity (MC) is the amount of information that can be hold in memory for a specific time interval. MC declines with aging and its decline is a form of mild cognitive impairment with high predictive value for conversion to dementia. Using the Different/Identical Object Recognition Task (DOT/IOT) that we have developed to study MC in rodents, we found that in conditions of high load female mice do not consolidate information into long-term memory. Here we report that this early highly specific deficit in memory consolidation predisposes female mice to an accelerated aging in memory performance; furthermore, we show that this MC deficit is related to estrogen-dependent impairment in GluA1 trafficking in the hippocampus, which we have previously shown to be important for MC in male mice (Sannino et al 2012, Olivito et al 2014). One-month voluntary exercise training, which is known to stimulate hippocampal function (Colcombe et al 2003), strikingly rescued the performance of aging female mice. In conclusion, we identified a cognitive marker of early aging in females, whose mechanisms may be at the base of their major vulnerability to AD. Furthermore, we show that this deficit is sensitive to exercise training, which makes it a valid model to study the molecular pathway underlying its therapeutic efficacy.