The Effects of Physical Running on Dendritic Spines and Amyloid-Beta Pathology in 3xTg-AD Male Mice

Abstract Background: Memory loss is the key symptom of Alzheimer's disease (AD). As successful drug treatments have not yet been identified, non-pharmaceutical intervention, such as physical exercise has been recognized as an effective strategy to improve memory function of people with dementia. Here we investigated the effect of prolonged physical running on hippocampal-dependent spatial memory and underlying mechanisms in 3xTg-AD mouse, a well-established rodent model of Alzheimer's disease (AD). Methods: 3xTg-AD transgenic mice with three AD mutations were used and compared with non-transgenic mice. Voluntary wheel running continued for 5 months (1 hour per day, 5 days per week) and was followed by spatial memory testing. At the end of behavior testing, dendritic spines, synapses, and synaptic proteins as well as amyloid-beta (Aβ) pathology were analyzed in the dorsal hippocampi. Results: Running improved hippocampal-dependent spatial memory in 3xTg-AD mice. This running strategy prevented both thin and mushroom-type spines on CA1 pyramidal cells in 3xTg-AD mice, whereas the effects of running in non-transgenic mice were limited to thin spines. The enormous effects of running on spines were accompanied by increased synapses and higher expressions of synaptic proteins. Notably, running downregulated the processing of amyloid precursor protein, resulting in reduced Aβ peptides, and spatial memory performance correlated with levels of Aβ peptides Aβ1-40 and Aβ1-42. Conclusion: These data suggest that prolonged running may improve memory in preclinical AD via slowing down amyloid pathology and preventing loss of synaptic contacts.