Abstract
Perturbations in metabolism results in the accumulation of beta-amyloid peptides, which is a pathological feature of Alzheimer’s disease. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate limiting enzyme responsible for beta-amyloid production. Obesogenic diets increase BACE1 while exercise reduces BACE1 activity, although the mechanisms are unknown. Brain-derived neurotropic factor (BDNF) is an exercise inducible neurotrophic factor, however, it is unknown if BDNF is related to the effects of exercise on BACE1. The purpose of this study was to determine the direct effect of BDNF on BACE1 activity and to examine neuronal pathways induced by exercise. C57BL/6J male mice were assigned to either a low (n = 36) or high fat diet (n = 36) for 10 weeks. To determine the direct effect of BDNF on BACE1, a subset of mice (low fat diet = 12 and high fat diet n = 12) were used for an explant experiment where the brain tissue was directly treated with BDNF (100 ng/ml) for 30 min. To examine neuronal pathways activated with exercise, mice remained sedentary (n = 12) or underwent an acute bout of treadmill running at 15 m/min with a 5% incline for 120 min (n = 12). The prefrontal cortex and hippocampus were collected 2-h post-exercise. Direct treatment with BDNF resulted in reductions in BACE1 activity in the prefrontal cortex (p < 0.05), but not the hippocampus. The high fat diet reduced BDNF content in the hippocampus; however, the acute bout of exercise increased BDNF in the prefrontal cortex (p < 0.05). These novel findings demonstrate the region specific differences in exercise induced BDNF in lean and obese mice and show that BDNF can reduce BACE1 activity, independent of other exercise-induced alterations. This work demonstrates a previously unknown link between BDNF and BACE1 regulation.
Highlights
Clinical and epidemiological evidence highlights the fact that lifestyle factors, such as diet and exercise, are crucial in reducing the risk of late onset Alzheimer’s disease (de la Monte and Wands, 2008; Pasinetti and Eberstein, 2008; Vagelatos and Eslick, 2013; Baranowski et al, 2018b, 2020)
BACE Activity Assay To establish if there is a direct link between Brain-derived neurotropic factor (BDNF) and Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a beta-secretase activity assay was performed on prefrontal cortex and hippocampus samples after a 30 min treatment with a 100 ng/ml dose of BDNF post-dissection
Results from this study demonstrate a novel link between BDNF and BACE1 activity
Summary
Clinical and epidemiological evidence highlights the fact that lifestyle factors, such as diet and exercise, are crucial in reducing the risk of late onset Alzheimer’s disease (de la Monte and Wands, 2008; Pasinetti and Eberstein, 2008; Vagelatos and Eslick, 2013; Baranowski et al, 2018b, 2020). In support of a direct effect of exercise on the brain, recent work from our lab examined whether an acute bout of exercise could reduce BACE1 activity and/or content after 7 weeks of high fat feeding, similar to that seen with long-term exercise training. These studies revealed that a single bout of exercise was able to reduce BACE1 content and activity in the brains of obese mice J. et al, 2019); the exact physiological mechanisms behind the exercise-induced reductions of BACE1 are unknown
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