Abstract
Obesity and insulin resistance are risk factors in the development of neurodegenerative disorders. Previous work suggests that one acute bout of exercise may have beneficial neuro‐protective effects in obese mice. The rate limiting enzyme in the production of amyloid‐beta peptides, BACE1, was reduced in the prefrontal cortex 2 h post‐exercise, however if these effects remain over time is unknown. We aimed to determine how long exercise–induced alterations persist in the prefrontal cortex and hippocampus following a single exercise bout. Male C57BL/6J mice were fed either a low (LFD, 10% kcals from lard) or a high fat diet (HFD, 60% kcals from lard) for 7 weeks. HFD mice then underwent an acute bout of treadmill running (15 m/min, 5% incline, 120 min) followed by 2‐, 8‐, or 24‐h of recovery. The HFD increased body mass (LFD 27.8 ± 1.05 vs. HFD 41.7 ± 0.60 g; P < 0.05) and glucose intolerance (AUC LFD 63.27 ± 4.5 vs. HFD 128.9 ± 4.6; P < 0.05). Prefrontal cortex BACE1 content was reduced 2‐ and 8‐h post‐exercise compared to sedentary HFD mice, however BACE1 protein content at 24 h was not different. Hippocampal BACE1 content was reduced 8‐ and 24‐h post‐exercise. Compared to the LFD, the HFD had higher prefrontal cortex phosphorylation of p38, JNK, and AMPK, indicative of increased neuronal stress. Post–exercise prefrontal cortex p38 and JNK phosphorylation were no different between the HFD or LFD groups, while ERK phosphorylation was significantly reduced by 24 h. The HFD increased JNK phosphorylation in the hippocampus. These results demonstrate the direct and potent effects of exercise on reducing BACE1 prefrontal cortex and hippocampal content. However the reduction in prefrontal cortex BACE1 content is short lived.
Highlights
Midlife obesity and insulin resistance are known risk factors for later-life development of dementia and Alzheimer’s disease (AD) (Beydoun et al 2008; Profenno et al 2010)
Following an intraperitoneal glucose injection, the high fat diet (HFD) mice cleared glucose less effectively and had a higher glucose area under the curve (AUC) compared to LFD mice (Fig. 1B, P < 0.0001). These results demonstrate that 7 weeks of a HFD resulted in obese, glucose intolerant mice
Exercise lowered BACE1 protein content 2 and 8 h post- compared to the HFD group (Fig. 2A, ANOVA, P = 0.0094; HFD vs. 2 h P = 0.0087, HFD vs. 8 h P = 0.0352). 24 h post-exercise BACE1 content was not different from the HFD group, indicating that reductions in BACE1 content in the prefrontal cortex are transient
Summary
Midlife obesity and insulin resistance are known risk factors for later-life development of dementia and Alzheimer’s disease (AD) (Beydoun et al 2008; Profenno et al 2010). Exercise training is well known to improve body composition, glucose and insulin tolerance/sensitivity, as well as improve markers of neurodegeneration (Colcombe et al 2004; Maesako et al 2012a,b), the exact cellular and molecular mechanisms underlying the beneficial effects of exercise on neurodegenerative disease remain elusive. It is unknown how much or how frequently one might need to exercise in order to reap neuro-protective benefits.
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