Mislocalized tau impairs dendritic endosome-lysosome and autophagy flux, trapping tau species in the somatodendritic compartment and sustaining synaptotoxic signaling after Aβ has been removed. This is best viewed as a persistence amplifier rather than the leading initiating mechanism.
Curated pathway from expert analysis
flowchart TD
A["MAPT/Tau Protein<br/>Microtubule Stabilizer"]
B["CDK5/GSK3B Activation<br/>Kinase Dysregulation"]
C["Tau Hyperphosphorylation<br/>Ser396/Thr231/Ser202"]
D["Tau Detachment<br/>Microtubule Destabilized"]
E["Tau Oligomers<br/>Paired Helical Filaments"]
F["Neurofibrillary Tangles<br/>Intraneuronal Inclusions"]
G["Axonal Transport Failure<br/>Synaptic Dysfunction"]
H["Neurodegeneration<br/>Tauopathy Spread"]
A --> B
B --> C
C --> D
D --> E
E --> F
D --> G
G --> H
F --> H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for MAPT,RAB5,RAB7,LAMP1,TFEB 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,RAB5,RAB7,LAMP1,TFEB.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF early-life Aβ pathology is pharmacologically cleared (via anti-Aβ antibody or BACE inhibitor) in 5xFAD mice but somatodendritic RAB7 and LAMP1 activity remains impaired, THEN phosphorylated tau acc | Sustained dendritic tau accumulation despite Aβ removal | — no observation — | pending | 0.55 |
| IF TFEB is selectively overexpressed in primary neurons from hMAPT transgenic mice to enhance endolysosomal and autophagy flux in the somatodendritic compartment, THEN dendritic tau mislocalization (m | Reduced somatodendritic tau accumulation with restored synaptic protein levels | — no observation — | pending | 0.65 |