Investigating mechanisms of oxidative-stress induced BDNF axonal transport deficits in basal forebrain cholinergic neurons
Bibliographic record
Abstract
Aging and Alzheimer’s disease (AD) are associated with decreased cognitive function and neural degeneration. The basal forebrain is one of the first areas of the brain to degenerate in AD and depends on the neurotrophin brain-derived neurotrophic factor (BDNF) for survival. Loss of BDNF transport from target neurons may contribute to basal forebrain cholinergic neuron (BFCN) vulnerability in AD and aging. Oxidative stress is associated with cholinergic dysfunction and cognitive decline in aging and AD, and it is possible that oxidative stress may contribute to BDNF transport deficits in BFCNs. BFCNs are grown in microfluidic chambers that allow isolation of BFCN soma and axon terminals so transport of biotinylated and fluorescently labelled BDNF can be quantified. The objective of my research was to determine if oxidative stress induces BDNF retrograde transport deficits in BFCNs, and the mechanism behind this effect. I found that oxidative stress does reduce BDNF retrograde transport in BFCNs. Because it has previously been shown that aged BFCNs have decreased BDNF transport and downregulate the BDNF receptor TrkB, expression of both TrkB and p75NTR receptors was tested following oxidative stress using immunocytochemistry (ICC) and western blotting. This experiment showed that oxidative stress does not affect p75NTR or TrkB receptor levels. A likely alternative is that oxidative stress may lead to alterations in the transport machinery responsible for retrograde BDNF transport. I hypothesized that oxidative stress decreases retrograde axonal transport of BDNF via increased insulin-like growth factor 1 receptor (IGF1R) activity, which decreases the protein expression of the adaptor proteins BICD1 and Hook1 by inhibiting GSK3β activity via the PI3K-Akt pathway. ICC and western blotting showed that oxidative stress has no effect on either BICD1 or Hook1 levels. Future directions of this work involve further studying the involvement of the IGF1R pathway in oxidative stress, and the effect on other proteins involved in BDNF transport, including htt and DISC1.
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".