Modification of tau pathology by yeast prion seeding and tau oligomer expression
Bibliographic record
Abstract
Neurodegenerative disorders are a mayor health risk for the aging population of the world. The aggregation of tau constitutes a mayor hallmark of Alzheimer disease (AD) and other neurological diseases such as progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementias with parkinsonism liked to chromosome 17. Tau spreads in a prion like manner via the formation of disease specific fibrils. The cause of tau aggregation in neurodegenerative disorders has yet remained unclear. We were now able to show, that the archaic yeast prion domain Sup35NM is able to cross-species cross-seed human tau. In tau transgenic P301S mice this led to an accentuation of tau pathology in the hippocampus of Sup35NM inoculated mice. In vitro seeding of tau monomers with Sup35NM fibrils led to the accelerated formation of tau fibrils. These fibrils showed a characteristic corkscrew-like pattern. In AD, early tau aggregation occurs in the olfactory bulb. The nasal sensors are in close contact to exogenous agents and the microbiome present in the nasopharyngeal cavity, and they are anatomically connected to the limbic system, which is also affected early in AD. Together our results allow a novel perception of the prion world, in which archaic prions of the human microbiome are able to influence the aggregation of prion-like proteins like tau in neurodegenerative diseases. Understanding the initiation of prion formation in sporadic neurodegenerative disorders will be pivotal for the long-awaited generation of preventive or curative approaches for these devastating disorders. \nAnother important aspect concerning the desired treatment of neurodegenerative diseases like tauopathies is the potential long term effect of neurotoxic stress caused by misfolded proteins like tau. We therefore investigated the long term effects of severe early neurotoxic tau stress in recovered transgenic P301SxTau62 mice. Counterintuitively, P301SxTAU62 tau mice which underwent transient severe paralysis in early life, and maintained their P301S tau expression, developed less tau pathology and even maintained a slightly better motor performance when aging, in comparison to their heterozygous P301S transgenic littermates, which were not exposed to early tau stress. In accordance with that, different from tau fibrils the tau oligomers detected in the brains of P301SxTAU62 tau mice were not able to cause tau fibrillization in human tau transgenic ALZ17 mice. This is further evidence, that the structure of tau aggregates plays a crucial role when it comes to tau pathology spreading in the brain via prion-like template transmission. It also speaks for the development of therapies which target tau before the formation of tau fibrils was initiated. \n \n
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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 | 0.000 | 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 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".