ROLE OF ACUTE EXERCISE-INDUCED BRAIN BDNF ON APP PROCESSING AND BACE1

Abstract

Perturbations in metabolism results in the accumulation of beta-amyloid, which is a pathological feature of Alzheimer's Disease (AD) (1). Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate limiting enzyme in the pathway responsible for beta-amyloid production (2). Exercise has been shown to reduce BACE1 activity, although the exact neurobiological mechanisms responsible are unknown (3). Exercise has also been shown to increase brain-derived neurotropic factor (BDNF) content and signaling (4), however whether this neurotrophic factor mediates the effects of exercise on BACE1 regulation requires further investigation. C57BL6 male mice were placed on a low (LFD; n=24) or high fat diet (HFD; n=24) for 10-weeks. Following the intervention, the mice either remained sedentary (n=12) or underwent an acute bout of treadmill running (n=12), proceeded by glucose/insulin tolerance tests and a Barnes maze test (spatial memory). Mice were euthanized and the prefrontal cortex was collected for protein quantification. Markers of the amyloidogenic pathway, along with targets of the BDNF signaling pathway, were examined. The 10-week HFD intervention led to increased body mass, inguinal and epididymal white adipose tissue mass, and liver mass (p < 0.05). HFD groups had impairments in glucose and insulin tolerance, as well as spatial memory (time in incorrect zones) (p < 0.05). A HFD led to increases in Akt phosphorylation (insulin signalling) and decreases in ERK phosphorylation (downstream of BDNF) (p < 0.05). An acute bout of exercise was able to recover ERK phosphorylation in the HFD group (p < 0.05) and significantly increase BDNF protein content in both LFD and HFD groups (p < 0.05). However, there were no changes in BACE1 protein content with diet or exercise (p > 0.05). Results from this study suggest that exercise can increase BDNF protein content in an obesogenic rodent model. Furthermore, a HFD potentially contributes to memory impairments by aberrant insulin signalling and impairments in BDNF signalling, which can be recovered through exercise. Although BACE1 protein content did not change, future analysis will examine BACE1 activity. Through these mechanisms, we gain further insight into using BDNF, mediated through exercise, as a therapeutic intervention.