Aggregation Trumps Phosphorylation in Tau‐mediated Toxicity
Bibliographic record
Abstract
Abstract Background Disease‐modifying therapies for tauopathies like Alzheimer’s disease have targeted Tau hyperphosphorylation and aggregation, as both pathological changes are implicated in Tau‐mediated toxicity. However, the interplay between Tau hyperphosphorylation and aggregation, and their relative contribution towards overall Tau toxicity is not entirely understood. Method Leveraging the genetic tractability of Drosophila, we generated novel transgenic lines designed to manipulate Tau phosphorylation and aggregation to address these questions and unpick the relationship between these pathological changes. Tau accumulation and neurodegenerative phenotypes were visualised and quantified using Confocal and super resolution (Structured Illumination Microscopy, SIM) microscopy. Changes in total and phosphorylated Tau in Drosophila brain homogenates were also quantified by western blot analysis. Result We report profound neurodegeneration following expression of phospho‐mimicking human Tau, indicative that phosphorylation is a key driver of Tau toxicity in tauopathies. However, when Tau is rendered unable to aggregate, through deletion of a known aggregation motif, Tau toxicity was completely abolished even in the presence of phospho‐mimicking mutations. To phenocopy the neuroprotective effects of genetically suppressing aggregation, a peptide inhibitor that targets the same aggregation‐promoting motif, was also efficacious in significantly reducing Tau phenotypes throughout the lifespan of Tau expressing flies. Conclusion Our data demonstrates that Tau phosphorylation mediates neurodegeneration through a mechanism gated via Tau aggregation such that if hyperphosphorylated Tau cannot aggregate, it is no longer toxic. These results should inform the next generation of Tau therapeutics as suppression of Tau aggregation may have profound disease‐modifying potential without the need to clear pathogenic phosphorylated species. Funded by Alzheimer’s Society of Canada and Mike & Valeria Rosenbloom Foundation Research Award: Award Number: AWD‐019542 ALZSOCCA 2020o.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.000 | 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 | 0.001 |
| 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".