Investigating the role of Brain Derived Neurotrophic Factor content and signalling on Amyloid Precursor Protein processing
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".