Transient Aβ exposure activates local kinase programs, especially CDK5/p25 and possibly GSK3β, that keep tau phosphorylated at missorting-associated epitopes. This would create a cell-autonomous phospho-tau maintenance state that survives Aβ withdrawal.
Curated pathway from expert analysis
flowchart TD
A["Target Gene: MAPTCDK5CAPN1GSK3B"]
B["Molecular Mechanism<br/>Pathway Activation"]
C["Cellular Phenotype<br/>Neuronal / Glial Response"]
D["Network Effect<br/>Circuit-Level Consequence"]
E["Disease Relevance<br/>Neurodegeneration Link"]
A --> B --> C --> D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for MAPT,CDK5,CAPN1,GSK3B from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for MAPT,CDK5,CAPN1,GSK3B.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF human iPSC-derived neurons expressing MAPT are transiently exposed to oligomeric Aβ42 (5 μM, 6 hours) followed by washout and subsequent CDK5 inhibition (roscovitine, 10 μM) at 24-48 hours post-wit | Significant reduction in dendritic phospho-tau (AT8/PHF-1) fluorescence intensity in the CDK5 inhibition group compared to Aβ-withdrawal-only group, with effect | — no observation — | pending | 0.00 |
| IF primary neurons from CDK5 conditional knockout (CDK5-floxed; CAMKIIa-Cre) mice are exposed to Aβ42 (5 μM, 6 hours) followed by washout, THEN dendritic missorting of phospho-tau will be prevented or | Significant reduction in dendritic phospho-tau accumulation in CDK5 knockout neurons relative to wildtype controls, with at least 50% lower AT8 immunoreactivity | — no observation — | pending | 0.00 |