Investigating the role of Brain Derived Neurotrophic Factor content and signalling on Amyloid Precursor Protein processing

Abstract

Alzheimer’s disease (AD) is a progressive, multifactorial, neurodegenerative disorder putatively linked to aging. The major pathological hallmark of AD is amyloid-β (Aβ) plaques, which is regulated through the activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). As such, understanding BACE1 regulation is crucial in the development of AD preventive strategies. It has been demonstrated that an acute bout of exercise can reduce BACE1 activity and content; however, the mechanism behind this regulation is unknown. One potential mediator of the exercise-induced reductions of BACE1 is brain-derived neurotrophic factor (BDNF). Studies indicate that exercise-induced changes in cognition and neuronal health require the synthesis, release, and binding of BDNF to its receptor. However, in AD, there is a reduction in synaptic plasticity, cognitive function, and BDNF content. The purpose of this thesis was to determine a viable method to elevate BDNF levels to modulate BACE1 activity and to determine the exact mechanisms by which BDNF can elicit this effect. In study 1 we aimed to determine if subcutaneous injections of recombinant BDNF would elicit a similar effect on amyloid precursor protein (APP) processing as observed with exercise. I found that peripheral BDNF injections improved cognitive performance, reduced BACE1 activity in the prefrontal cortex. In study 2, we explored a potential dietary intervention that may influence BDNF levels. Elevated beta-hydroxybutyrate (β-OHB) levels were previously established to elevate BDNF through epigenetic modifications. Therefore, we examined the effect of oral β-OHB supplementation on BDNF and (APP) processing. I determined that β-OHB supplementation was ineffective at elevating BDNF levels and did not improve cognition. However, β-OHB supplementation did reduce BACE1 activity. Finally, despite demonstrating a link between BDNF and BACE1 activity, the exact mechanism connecting them has remained elusive. The final purpose of this thesis was to examine how BDNF can modulate BACE1 activity. I conclude that BDNF appears to be eliciting a regulatory role on BACE1 activity through GSK3β inhibition. Taken together, this thesis highlights potential therapeutic strategies to target BACE1 modulation and elucidates a mechanism by which BDNF acts, thus allowing for more targeted therapeutic approaches in the future.