The NGF Metabolic Pathway is altered in a Rat Model of Human‐like Tauopathy
Bibliographic record
Abstract
BACKGROUND: Cholinergic signaling is crucial for learning, memory, and attention. In Alzheimer's disease (AD) the degeneration of basal forebrain cholinergic neurons (BFCNs) is a key pathological feature driven by an impaired maturation of nerve growth factor (NGF). Our lab identified the NGF metabolic pathway, which regulates mature NGF (mNGF) availability, and demonstrated its dysregulation in human AD brain tissue and biofluids, as well as in amyloid pathology rat models. However, the impact of tau pathology-another AD hallmark-on cholinergic dysfunction is not well understood. This study aims to determine how tau pathology affects the NGF pathway and cholinergic function. METHOD: We examined NGF pathway proteins in cortical and hippocampal samples from homozygous McGill-R955-hTau transgenic rats, which model tauopathy. At 10 months, R955-hTau rats show tau hyperphosphorylation and social behavior deficits. By 14 months, tau misfolding, aggregation, NFT-like inclusions, glial activation, and cognitive impairments emerge. At 20 months, advanced tau pathology includes neuronal loss, brain atrophy, and myelin and vascular abnormalities. NGF pathway protein levels were assessed at 9, 14, and 20 months using Western blot and ELISA. Cholinergic bouton density in the parietal cortex of 20-month-old rats was assessed with a VAChT antibody, and BFCNs density and size were measured with a ChAT antibody. RESULT: In 20-month-old R955-hTau rats with advanced tauopathy, we observed a significant increase in neuroserpin and proNGF levels, along with a decrease in mNGF levels. This NGF dysregulation was absent in younger rats, indicating that alterations in the NGF pathway occur later in tau pathology. Preliminary analyses also revealed disruptions in other NGF pathway components and reduced cortical VAChT immunoreactivity suggesting a consequential cholinergic atrophy. CONCLUSION: Our studies in McGill-R955-hTau rats would indicate that the advanced tauopathy provokes an additional dysregulation of the brain's NGF metabolic pathway leading to an exacerbated forebrain cholinergic atrophy.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".