MAPT tau seeding and release across AD, FTD, and PD-spectrum disease
🧪 Overview
Shared mechanism across AD, FTD, PD: MAPT dysfunction creates a tau species that can detach from microtubules, aggregate, and spread through vulnerable circuits; AD emphasizes amyloid-primed tau spread, FTD shows primary MAPT mutation/tauopathy, and PD-linked LRRK2 can increase tau accumulation, aggregation, and release.
Falsifiable prediction: LRRK2 kinase inhibition should reduce extracellular tau release by at least 20% in MAPT-mutant cortical neurons and in alpha-synuclein-stressed dopaminergic neurons, with phospho-tau reduction tracking kinase target engagement.
Proposed experiment: Culture MAPT-mutant FTD neurons, AD tau-seeding organoids, and LRRK2-G2019S dopaminergic neurons; apply a selective LRRK2 inhibitor; measure p-tau, seeded biosensor activity, EV-associated tau release, and synaptic integrity.
Cross-disease confidence rationale: Strong genetic FTD tau evidence plus mechanistic LRRK2-tau bridge into PD.
Internal SciDEX support: SciDEX support query found 90 matching hypotheses across 8 disease labels, including 90 with debate_count > 0.
🧬 Mechanism
Auto-built from this analysis's top knowledge-graph edges.
graph TD
MAPT["MAPT"] -->|cross disease mech| AD["AD"]
MAPT_1["MAPT"] -->|cross disease mech| FTD["FTD"]
MAPT_2["MAPT"] -->|cross disease mech| PD["PD"]
h_cross_synth_mapt_tau_se["h-cross-synth-mapt-tau-seeding"] -->|proposes shared me| MAPT_3["MAPT"]
style MAPT fill:#4fc3f7,stroke:#333,color:#000
style AD fill:#ef5350,stroke:#333,color:#000
style MAPT_1 fill:#4fc3f7,stroke:#333,color:#000
style FTD fill:#ef5350,stroke:#333,color:#000
style MAPT_2 fill:#4fc3f7,stroke:#333,color:#000
style PD fill:#ef5350,stroke:#333,color:#000
style h_cross_synth_mapt_tau_se fill:#4fc3f7,stroke:#333,color:#000
style MAPT_3 fill:#4fc3f7,stroke:#333,color:#000⚖️ Evidence
🏥 Translation
🧬 3D Protein Structure — MAPT
💉 Clinical Trials
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.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| LRRK2 kinase inhibition should reduce extracellular tau release by at least 20% in MAPT-mutant cortical neurons and in alpha-synuclein-stressed dopaminergic neurons, with phospho-tau reduction trackin | If this mechanism is real, then LRRK2 kinase inhibition should reduce extracellular tau release by at least 20% in MAPT-mutant cortical neurons and in alpha-syn | — no observation — | pending | 0.82 |
▸Metadatasource: v1_phase_c_backfill · origin_type: cross_disease_synthesis
| source | v1_phase_c_backfill |
| origin_type | cross_disease_synthesis |
| _schema_version | 1 |