NERVE GROWTH FACTOR AND THE FOREBRAIN CHOLINERGIC PHENOTYPE IN THE PRE-CLINICAL-CLINICAL PROGRESSION OF THE ALZHEIMER’S DISEASE PATHOLOGY
Bibliographic record
Abstract
A. Claudio Cuello Pharmacology Therapeutics, McGill University -Visiting Professor Pharmacology Oxford University Our laboratory has discovered a novel brain metabolic pathway which explains the release of proNGF to the extracellular space and its conversion to mature NGF and the degradation of the remaining mature NGF unbound to receptors. We have validated pharmacologically this novel NGF metabolic pathway. Further to it, we have found it deregulated in the continuum of the Alzheimer’s disease (AD) pathology and in Down syndrome individuals. In summary: -Endogenous NGF regulates the day-to-day number of cortical cholinergic synapsesThe occurrence of an NGF metabolic pathway controlling the cholinergic phenotype of basal forebrain (BF) neurons and cortical synapses. -In AD pathology there is reduced conversion of proNGF to mature NGF (mNGF) and increased degradation of mNGF. -The NGF metabolic dysregulation in AD, signifies a deficiency in trophic support of BF cholinergic neurons, thus explaining their atrophy in this pathology. -The NGF pathway is dysregulated in Down Syndrome (DS) brains at both clinical and preclinical AD stages. -An NGF metabolic dysregulation is found in postmortem brain samples of non-cognitively impaired (NCI) individuals with incipient AD. The NGF dysmetabolism correlates with lower cognitive scores and diminished expression of cortical cholinergic markers (VAChT). -In DS body fluids proNGF levels are increasingly elevated in their transition from DS without clinical AD to DS with clinical AD and predict subsequent cognitive decline. IN CONCLUSION: Failure of the NGF metabolic pathway, even at preclinical AD stages, explains the trophic support loss sustaining NGF-dependent cholinergic neurons of the basal forebrain. The altered levels of key molecules of NGF metabolic pathway in body fluids, particularly elevated proNGF, could assist the identification of individuals at preclinical AD pathology stages. (Recent references: Alzheimers & Dement 17:605, 2021; Mol Psychiatry, 26:6023, 2021; Cells 11:16, 2021; Brain145:2250, 2022). None
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.010 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.003 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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 teacher head, 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".