P3‐394: Hyperphosphorylation and cleavage of tau at the C‐terminal enhance the secretion of tau
Bibliographic record
Abstract
It is well established that tau pathology propagates in a predictable manner in Alzheimer's disease (AD). Moreover, tau accumulates in the cerebrospinal fluid (CSF) of AD's patients. The mechanisms underlying the propagation of tau pathology and its accumulation in the CSF remain to be elucidated. Recent studies have reported that human tau was secreted by neurons and non-neuronal cells when it was overexpressed indicating that tau secretion could contribute to the spreading of tau pathology in the brain and could lead to its accumulation in the CSF. In the present study, we showed that the overexpression of human tau resulted in its secretion by Hela cells. Human tau fused to the GFP tag (GFP-tau) was overexpressed in Hela cells. Forty-eight hrs after transfection, tau expression was analyzed in the cell lysate and culture medium with several anti-tau antibodies. To demonstrate that the presence of tau in the culture medium was not caused by membrane leakage from dying cells but rather by an active process of secretion, three approaches were used. First, the presence of a cytosolic protein such as tubulin in the culture medium from control and cells overexpressing tau was analyzed. Second, cell death was evaluated by the Trypan blue exclusion method and by the lactate dehydrogenase (LDH) activity measurement in the medium. Third, to demonstrate that tau was secreted by an active process by Hela cells, the secretion of tau was examined when the cells were incubated at low temperature, a condition known to decrease secretion by exocytosis. The main form of tau secreted by these cells was cleaved at the C-terminal. Secreted tau was phosphorylated at several sites as reported for tau found in the CSF. Our data also revealed that the mimicking of phosphorylation at 12 sites known to be phosphorylated in AD enhanced tau secretion. Similarly, when tau was cleaved at the C-terminal, a significant increase of tau secretion was observed. Taken together, our results indicate that hyperphosphorylation and cleavage of tau by favoring its secretion could contribute to the propagation of tau pathology in the brain and its accumulation in the CSF.
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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 | 0.001 |
| 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) | 0.003 | 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".