Characterization of Cholinergic System Dysregulation in the McGill‐R955‐hTau Rat Model of Human‐Like Tauopathy
Bibliographic record
Abstract
BACKGROUND: Alzheimer's disease (AD), the most prevalent tauopathy, affects 6.7 million individuals aged 65 and older. While the retrograde atrophy of the basal forebrain cholinergic system is well-documented in AD patients and amyloidosis-based rodent models, the specific role of Tau pathology in cholinergic neurodegeneration remains poorly understood. This study utilized the McGill-R955-hTau rat model, which closely mirrors human-like tauopathy, to investigate the extent to which brain tauopathy contributes to cholinergic system dysregulation in the absence of brain amyloidosis. METHODS: Female and male 20-month-old homozygous transgenic and Wild-type (WT) rats were utilized. At this time-point, transgenic rats display Tau misfolding and aggregation into neurofibrillary tangle-like inclusions leading to cognitive impairments, brain atrophy, neuronal degeneration and gliosis. To assess the density of cholinergic terminations, varicosities expressing the vesicular acetylcholine transporter (VAChT) were quantified in the parietal cortex via immunohistochemistry. Given that the phenotypic maintenance of cholinergic neurons is regulated by the endogenous nerve growth factor (NGF), we further investigated key proteins of the NGF metabolic pathway using Western Blot and Enzyme-Linked Immunosorbent Assay. RESULTS: Immunohistochemistry analyses point to a reduction in VAChT immunoreactive varicosities in McGill-R955-hTau transgenic rats compared to WT controls, indicating diminished cholinergic innervation in the cortex. Compared to WT littermates, transgenic rats also exhibited significantly reduced levels of mature NGF, underscoring a compromised trophic support necessary for the phenotypic maintenance of cholinergic neurons. In line with the above, proNGF and Neuroserpin levels were elevated in the Tau transgenic rats relative to WT controls, suggesting impaired conversion of proNGF into mature NGF. CONCLUSION: The McGill-R955-hTau rat model demonstrates cholinergic dysfunction at advanced stages of brain tauopathy, independent of amyloidosis. Our findings highlight a tau-mediated cholinergic synaptic loss and an accelerated dysregulation of the NGF metabolic pathway previously linked only to amyloidosis or neuroinflammation. These findings offer a further insight into the mechanistic relationship between tauopathy and cholinergic system atrophy in the progression of AD pathology.
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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) | 0.002 | 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".