Tau pathology in triple knock‐in mouse model of Alzheimer's Disease expressing APOE3 and APOE4
Bibliographic record
Abstract
Abstract Background Tau is a microtubule stabilizing protein that becomes dysfunctional during the course of Alzheimer's Disease. Previous research has shown that individually amyloid and APOE4 have the potential to increase tau phosphorylation and worsen tau pathology in tau mutant models of tauopathy. However, whether both amyloid and APOE4 can further contribute to tau dysfunction in mouse models that more faithfully reflect the levels of tau in humans is unknown. We developed mouse models with a combination of incorporated humanized knock‐in variants of hMAPT, App NL and App NL‐F and APOE 3 or APOE 4 genotypes. Method Biochemical and imaging techniques including immunofluorescence microscopy and Western Blots were performed for phosphorylated tau at the Serine 202/Threonine 205 sites (AT8) and total tau. Visuospatial learning and memory were assessed using the Paired Associates Learning (PAL) task, an automated touchscreen task. Result Our preliminary results indicated that tau protein phosphorylated at the Serine 202/Threonine 205 phosphorylation site is detected in in both male and female mice in a genotype dependent manner. Aging, expression of App NL‐F and APOE4 increased tau phosphorylation. Insoluble total tau was found predominantly in aged mice (18 months) and was worse in APOE4 expressing individuals. All the antibodies used detected no signal in tissue from tau knockout mice confirming the results are a consequence of changes in tau. Preliminary results indicate that 12‐month old App NL and App NL‐F mice (ApoE3 and ApoE4) were able to learn the PAL task to 70% accuracy. There were no genotype‐dependent differences in performance. Conclusion The results of this project demonstrate that tau pathology markers appear to increase as a function of age, APOE4 and the ability to accumulate insoluble Abeta and plaques . These results agree with the notion that amyloid and APOE4 can increase tau markers even in less aggressive animal models without tau overexpression or mutations. Our findings also suggest that there are no genotype‐dependent differences in learning and memory in the PAL task at early ages, despite these mice presenting other cognitive deficits at that stage.
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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 | 0.001 | 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 | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".