Three weeks of running wheel exposure improves cognitive performance in the aged Tg2576 mouse

Abstract

If begun early in life, exercise effectively reduces the development of cognitive deficits in transgenic mouse models of Alzheimer's disease (AD). However, the effectiveness of exercise, once the cognitive impairments are established, is not as clear. In terms of translating research in animal models to treatments involving exercise in Alzheimer's disease patients, it is critical to evaluate exercise intervention at time points that address not only prevention, but also treatment of cognitive decline. We provided exercise wheels to Tg2576 (TG) (n=12) and C57BL6 (WT) (n=17) mice at 16-18 months of age for three weeks. At this age animals have significant cognitive impairment and neuropathology consistent with AD. Age matched sedentary TG (n=13) and WT (n=12) mice were also included, as well as groups provided access to an immobile wheel (TG n=9, WT n=12). After three weeks, animals were evaluated in a radial arm water maze. Significant impairments were observed in the sedentary TG mice compared to WT in reference/long-term and working/short-term memory, as well as in probe trials. Exercised TG mice demonstrated improvements in memory, which made them indistinguishable from WT mice on all tasks. In addition, animals provided with an immobile wheel exhibited improvement in some, but not all cognitive measures. Our findings demonstrate that exercise can improve cognitive performance in a mouse model of AD even if applied after the development of pathology.

Corticosterone and dopamine D2/D3 receptors mediate the motivation for voluntary wheel running in C57BL/6J mice

“…Novelty and environmental enrichment can also contribute to the positive effects of exercise [41] but this was not the case here. We showed previously that repeated exposure to a novel environment, which also induces physical exercise, improved memory in a mouse model of Alzheimer's disease but not in wild-type C57BL/6J mice [35,42,43] while exposure to a static wheel was sufficient to improve some cognitive measures in another Alzheimer's mouse model [44]. Altogether, this suggests that the enrichment aspect of exercise may only beneficial to cognitive performance in animals with pre-existing memory impairments.…”

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

“…Beneficial effects were observed following just three weeks of voluntary wheel running (Nichol et al, 2007) up to nine months of wheel running (Belarbi et al, 2011). Exercising mice on treadmills also resulted in gains when mice were trained for five weeks (Ke et al, 2011) up to five months (Bo et al, 2014;Zhao et al, 2015).…”

Impaired Adaptive Cellular Responses to Oxidative Stress and the Pathogenesis of Alzheimer's Disease

“…In old Tg2576 mice, access to a running wheel for 13 weeks improved memory to levels similar to nontransgenic animals (125). Other studies found that as little as 3 weeks' running in 15-19-month-old Tg2576 mice, a time point where significant AD pathology has begun, was able to improve spatial learning (129) and decrease level soluble forms of A beta (126).…”

“…Exercise has also been shown to be beneficial to mouse models of AD (3,(124)(125)(126). In old Tg2576 mice, access to a running wheel for 13 weeks improved memory to levels similar to nontransgenic animals (125).…”

“…Activation of adaptive stress responses in animal models of neurodegenerative diseases have been able to provide benefits in cognition and motor function, and suggest that these molecular pathways maybe able to be activated through cognitive stimulation, exercise, and CR (41,42,67,76,108,125). One of the key factors that may help protect against the decline of cognitive function in aging and disease is BDNF.…”