ID: h-e3557d75fa56
Hypothesis
Tau dysfunction destabilizes labile pool
Loss of tau function (as in disease states) selectively destabilizes the labile microtubule population, disrupting axonal transport while sparing stable domains.
EvidenceStrong (70%)📖 6 cit🗣 1 debates✓ 6 support✗ 2 oppose
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🧪 Overview
Loss of tau function (as in disease states) selectively destabilizes the labile microtubule population, disrupting axonal transport while sparing stable domains
Prediction: Tau-targeted interventions will selectively impair transport of organelles requiring labile microtubules (mitochondria, endosomes) while sparing lysosome transport
🧬 Mechanism
🧬 Curated Mechanism Pathway
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:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix6 supports1 contradicts
Supports
Loss of tau function (as in disease states) selectively destabilizes the labile microtubule population, disrupting axonal transport while sparing stable domains
Supports
MAPT mutations, tauopathy, and mechanisms of neurodegeneration.
Supports
Endolysosomal impairment by binding of amyloid beta or MAPT/Tau to V-ATPase and rescue via the HYAL-CD44 axis in Alzheimer disease.
Supports
Tau-targeting antisense oligonucleotide MAPT(Rx) in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial.
Supports
ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.
Supports
The six brain-specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes.
Contradicts
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — MAPT
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for MAPT from GTEx v10.
💉 Clinical Trials (5)Relevance: 85%
0
Active
Active
0
Completed
Completed
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Total Enrolled
Total Enrolled
PHASE1
Highest Phase
Highest Phase
COMPLETED·NCT06584656 · Universidad de Granada
Healthy Aging Cognitive Function 1, Social Cerebrovascular Circulation
Aerobic exercise condition Resistance exercise condition
Safety Study of AADvac1, a Tau Peptide-KLH-Conjugate Active Vaccine to Treat Alzheimer's DiseasePHASE1
COMPLETED·NCT01850238 · Axon Neuroscience SE
Alzheimer Disease
AADvac1 Placebo
RECRUITING·NCT04906863 · Columbia University
Dementia, Early Onset
Blood draw Neurocognitive testing Medical questionnaire
COMPLETED·NCT04413344 · Kyoto University
Familial Alzheimer Disease (FAD) PSEN1 Mutation
Bromocriptine Mesilate Placebos
COMPLETED·NCT03978052 · Parc de Salut Mar
Alzheimer Disease Cognitive Decline
EGCG Placebo EGCG Healthy lifestyle recommendations
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
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
▼ 0.4%
Volatility
High
0.1386
Events (7d)
2
Price History
▼6.8%💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF CRISPR/Cas9-mediated MAPT knockout is performed in human iPSC-derived cortical neurons, THEN the mean anterograde velocity of mitochondria in distal axons will decrease by at least 40% relative to | Selective ≥40% decrease in mitochondrial transport without significant change in lysosome transport. | — no observation — | pending | 0.60 |
| IF a selective labile microtubule stabilizer (e.g., 10 nM epothilone D) is applied to MAPT knockout neurons, THEN the mitochondrial transport deficit will be rescued to ≥80% of wild-type velocity with | Restoration of mitochondrial transport velocity to ≥80% of wild-type levels after epothilone D. | — no observation — | pending | 0.55 |
🔮 Falsifiable Predictions (2)
pendingconf 60%
IF CRISPR/Cas9-mediated MAPT knockout is performed in human iPSC-derived cortical neurons, THEN the mean anterograde velocity of mitochondria in distal axons will decrease by at least 40% relative to wild-type controls within 10 days, while the velocity of lysosomes will not change by more than 15%.
Predicted outcome: Selective ≥40% decrease in mitochondrial transport without significant change in lysosome transport.
Falsification: If both mitochondrial and lysosome transport are reduced by ≥30% or if mitochondrial transport reduction is <30%, the hypothesis of selective destabilization of labile microtubules is falsified.
pendingconf 55%
IF a selective labile microtubule stabilizer (e.g., 10 nM epothilone D) is applied to MAPT knockout neurons, THEN the mitochondrial transport deficit will be rescued to ≥80% of wild-type velocity within 48 h of treatment.
Predicted outcome: Restoration of mitochondrial transport velocity to ≥80% of wild-type levels after epothilone D.
Falsification: If mitochondrial transport remains <50% of wild-type after 48 h of epothilone D treatment, the hypothesis that labile microtubule destabilization underlies the transport deficit is falsified.
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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