White matter degeneration precedes tau aggregation in rats with Alzheimer's-like tauopathy
Bibliographic record
Abstract
Tau pathology is increasingly recognized as a primary driver of white matter (WM) microstructural damage in tauopathies, particularly in Alzheimer's disease. However, whether WM degeneration precedes detectable tau tangle deposition remains unclear. In this study, we used the McGill-R955-hTau transgenic rat model to investigate the temporal relationship between tau pathology and WM degeneration. In 12-month-old R955-hTau rats, early tau pathology was restricted to cortical neurons and characterized by phosphorylated tau accumulation and diffuse PHF1 immunoreactivity, in the absence of neurofibrillary aggregates and neuronal loss. Despite the absence of tau pathology in the WM, the corpus callosum exhibited significant atrophy, early axonal damage, and myelin fragmentation. These changes were accompanied by heightened glial activation, increased microglial phagocytic activity, and oligodendrocyte proliferation, without a net increase in total oligodendrocyte numbers. This early WM degeneration, occurring distal to tau accumulation, was associated with subtle social behavior deficits. At more advanced stages, R955-hTau rats displayed aggregated neurofibrillary tau, and the tau pathology spread into the WM. This exacerbated WM atrophy, axonal and myelin degeneration, oligodendrocyte proliferation, glial activation, and cognitive impairments. These findings reveal that initial WM pathology occurs independently of WM tau deposition and progresses alongside worsening grey matter tau pathology and its spread into the WM. These changes closely paralleled the onset and progression of cognitive decline. Overall, our results highlight WM degeneration as an early and significant consequence of grey matter tauopathy, suggesting that early therapeutic approaches targeting grey matter tauopathy should improve cognitive outcomes and help preserve both neuronal networks and WM integrity. • Human tau spreads from the grey to the white matter (WM) in aged R955-hTau rats. • WM atrophy occurs before cortical tau aggregation and WM tau pathology. • Axonal damage, myelin fragmentation, and glial activation mark early WM changes. • Myelin damage elicits oligodendrocyte proliferation and maturation. • WM degeneration correlates with cognitive deficits and the extent of tau 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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".