Reduced cortical BACE1 content with one bout of exercise is accompanied by declines in AMPK, Akt, and MAPK signaling in obese, glucose-intolerant mice

Abstract

Obesity and type 2 diabetes are significant risk factors in the development of neurodegenerative diseases, such as Alzheimer's disease. A variety of cellular mechanisms, such as altered Akt and AMPK and increased inflammatory signaling, contribute to neurodegeneration. Exercise training can improve markers of neurodegeneration, but the underlying mechanisms remain unknown. The purpose of this study was to determine the effects of a single bout of exercise on markers of neurodegeneration and inflammation in brains from mice fed a high-fat diet. Male C57BL/6 mice were fed a low (LFD; 10% kcal from lard)- or a high-fat diet (HFD; 60% kcal from lard) for 7 wk. HFD mice underwent an acute bout of exercise (treadmill running: 15 m/min, 5% incline, 120 min) followed by a recovery period of 2 h. The HFD increased body mass and glucose intolerance (both P < 0.05). This was accompanied by an approximately twofold increase in the phosphorylation of Akt, ERK, and GSK in the cortex (P < 0.05). Following exercise, there was a decrease in beta-site amyloid precursor protein cleaving enzyme 1 (BACE1; P < 0.05) and activity (P < 0.001). This was accompanied by a reduction in AMPK phosphorylation, indicative of a decline in cellular stress (P < 0.05). Akt and ERK phosphorylation were decreased following exercise in HFD mice to a level similar to that of the LFD mice (P < 0.05). This study demonstrates that a single bout of exercise can reduce BACE1 content and activity independent of changes in adiposity. This effect is associated with reductions in Akt, ERK, and AMPK signaling in the cortex.

Palmitic Acid-BSA enhances Amyloid-β production through GPR40-mediated dual pathways in neuronal cells: Involvement of the Akt/mTOR/HIF-1α and Akt/NF-κB pathways

“…One study investigated the role of the PI3K/Akt pathway in APP processing suggesting that PI3K/Akt activation is associated with BACE1 expression in the brains of HFD-fed mice 55 . This finding is consistent with our data showing that the PI3K/Akt pathway is a key regulator of APP and BACE1 expressions in SK-N-MC cells treated with PA-BSA.…”

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

“…liver and triceps, respectively). Samples were then centrifuged at 1500 g (4°C) for 5 minutes (hypothalamus was centrifuged at 10,000 g for 15 minutes (MacPherson et al, 2015)), the supernatant was collected and a bicinchoninic acid (BCA) assay was performed to determine protein concentration (Smith et al, 1985). Separation of equal amounts of protein was completed using 10% SDS-PAGE gels followed by a wet transfer onto nitrocellulose membrane (100V for 60 minutes).…”

Evaluation of neuropathological effects of a high-fat high-sucrose diet in middle-aged male C57BL6/J mice

“…), while a recent study examined diet‐induced obesity and glucose intolerance in mice, demonstrated an increase in ERK phosphorylation and a trend for increased p38 phosphorylation (Macpherson et al. ). A 1 year high‐sugar high‐fat diet resulted in increases in beta‐amyloid content along with increased phosphorylated JNK in the hippocampus of rats as early as 6 months (Niu et al.…”

“…Work from our group has demonstrated that high‐fat feeding of wild‐type C57BL6/J mice results in an increase in BACE1 activity (Macpherson et al. ). Furthermore, several rodent models of diabetes (genetic, diet and streptozotocin induced) results in increased BACE1 content and beta‐amyloid generation in the brain (Li et al.…”

“…Rodent work has demonstrated an ~2‐fold increase in Akt phosphorylation in prefrontal cortex samples from young male C57BL6 mice (~16 weeks of age) following a high‐fat diet (Macpherson et al. ) as well as aged mice following 5 months of high‐fat feeding (Muller et al. ).…”