ProNGF and BDNF transport in basal forebrain neurons
Bibliographic record
Abstract
Neurotrophins such as pro-nerve growth factor (proNGF) and brain-derived neurotrophic factor (BDNF) are essential for survival and function of basal forebrain cholinergic neurons (BFCNs). ProNGF and BDNF exert their functions through the tropomyosin-related kinase (Trk) receptors, TrkA and TrkB, respectively, and the pan neurotrophin receptor, p75NTR. Neurotrophins binding to their receptors enables retrograde axonal transport, a process necessary for BFCNs to obtain neurotrophins. Neurotrophin transport is impaired in aging, which is associated with BFCN degeneration and cognitive decline. The mechanisms causing loss of neurotrophin transport are unknown. Nitrative stress is elevated in aging and increases JNK activation, but whether this affects neurotrophin transport has not previously been studied. This project investigated how nitrative stress affects proNGF and BDNF transport in BFCNs. BFCNs were cultured in microfluidic chambers and aged for 7-22 days in vitro. Quantum dot labelled proNGF, BDNF, and proNGF mutants that selectively bind to TrkA or p75NTR were added to BFCN axons prior to analysis of their retrograde transport via fluorescence microscopy. Nitrative stress was manipulated using L-NAME, a nitric oxide synthase inhibitor, DEA NONOate, a nitric oxide generator, and SIN-1, a peroxynitrite generator. JNK activity was inhibited using CC401. We determined that nitrative stress decreases retrograde transport of proNGF via TrkA while increasing proNGF transport via p75NTR, which is associated with decreased neurotrophic signalling, increased apoptotic signalling, and neurodegeneration. Additionally, nitrative stress impairs proNGF transport by activating JNK independently of p75NTR. Nitrative stress-induced JNK activation also impairs BDNF transport in young BFCNs but increases BDNF transport in aged BFCNs. Aged BFCNs have decreased levels of TrkB relative to young BFCNs, which may explain the differential effects of nitrative stress on BDNF transport in aged versus young neurons. These results indicate that nitrative stress-induced JNK activation contributes to loss of neurotrophin transport and BFCN degeneration in aging.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".