Physical activity delays hippocampal neurodegeneration and rescues memory deficits in an Alzheimer disease mouse model

Abstract

The evidence for a protective role of physical activity on the risk and progression of Alzheimer's disease (AD) has been growing in the last years. Here we studied the influence of a prolonged physical and cognitive stimulation on neurodegeneration, with special emphasis on hippocampal neuron loss and associated behavioral impairment in the Tg4-42 mouse model of AD. Tg4-42 mice overexpress Aβ4-42 without any mutations, and develop an age-dependent hippocampal neuron loss associated with a severe memory decline. We demonstrate that long-term voluntary exercise diminishes CA1 neuron loss and completely rescues spatial memory deficits in different experimental settings. This was accompanied by changes in the gene expression profile of Tg4-42 mice. Deep sequencing analysis revealed an upregulation of chaperones involved in endoplasmatic reticulum protein processing, which might be intimately linked to the beneficial effects seen upon long-term exercise. We believe that we provide evidence for the first time that enhanced physical activity counteracts neuron loss and behavioral deficits in a transgenic AD mouse model. The present findings underscore the relevance of increased physical activity as a potential strategy in the prevention of dementia.

Small heat shock proteins in neurodegenerative diseases

“…So, the lack of sHSPs seems to aggravate the Alzheimer's symptoms. In line with this, a transgenic Alzheimer's mouse model subjected to physical activity showed increased expression of HSPB5 accompanying the hippocampal improvements (Huttenrauch et al 2016). Crossing the APPswe/PS1dE9 mouse model for Alzheimer's disease with a mouse model that overexpresses HSPB1 led to significant improvements in spatial learning and electrophysiological parameters.…”

Acute exercise does not modify brain activity and memory performance in APP/PS1 mice

“…Similar translation studies from rodents [47] to humans [48] has proven successful for exercise as a protective measure against AD. Therefore, a simple diagnostic procedure derived from our observations and others [49], would consist in submitting test subjects to moderate exercise in conjunction with recording EEG activity before and after exercise.…”

Altered neurogenesis in mouse models of Alzheimer disease

“…[34][35][36] In the Tg4-42 model, enhanced physical activity using enriched housing in cages equipped with running wheels resulted in an amelioration of CA1 neuron loss, accompanied by a significantly increased overall dentate gyrus granule cell number and a concomitant increase in the number of DCX-positive cells in the DG. 26 So far, no accumulation of Ab peptides within dentate gyrus neurons has been reported in any of the mouse models that have been studied. The fact that many of the models that show alterations in neurogenesis also express substantial levels of mutant APP within this brain region (Fig.…”