ID: h-c704dd991041
Hypothesis
Tau/MAP6 ratio as a master switch for microtubule dynamics plasticity
The relative abundance of tau versus MAP6 on individual microtubules determines the balance between stable and labile domains, creating a spatial code for where dynamic remodeling (axon guidance, branching) versus stable support (process.
EvidenceStrong (70%)📖 6 cit🗣 1 debates✓ 6 support✗ 2 oppose
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🧪 Overview
The relative abundance of tau versus MAP6 on individual microtubules determines the balance between stable and labile domains, creating a spatial code for where dynamic remodeling (axon guidance, branching) versus stable support (process integrity) occurs
Prediction: Manipulating the tau:MAP6 expression ratio will shift the entire spectrum of neuronal plasticity phenotypes in a predictable dose-response manner
🧬 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 supports0 contradicts
Supports
The relative abundance of tau versus MAP6 on individual microtubules determines the balance between stable and labile domains, creating a spatial code for where dynamic remodeling (axon guidance, branching) versus stable support (process integrity) occurs
Supports
Antagonistic roles of tau and MAP6 in regulating neuronal development.
Supports
Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W.
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.
📖 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
0
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 MAPT-knockout neurons (which have low tau) are crossed with MAP6-knockout neurons to create a double knockout, THEN rescued expression of MAP6 at 3x endogenous levels will normalize axon branch dyn | Rescue with high MAP6 restores dynamic remodeling rates to wildtype baseline; rescue with low MAP6 leaves dynamics elevated | — no observation — | pending | 0.40 |
| IF the tau:MAP6 expression ratio is experimentally shifted via CRISPR activation of MAP6 promoter in mature hippocampal neurons (increasing MAP6 relative to endogenous tau), THEN microtubule dynamic i | Dose-dependent increase in microtubule dynamics (shorter EB3 comet lifetimes, increased catastrophe frequency) and decrease in stable acetylated microtubule net | — no observation — | pending | 0.45 |
🔮 Falsifiable Predictions (2)
pendingconf 45%
IF the tau:MAP6 expression ratio is experimentally shifted via CRISPR activation of MAP6 promoter in mature hippocampal neurons (increasing MAP6 relative to endogenous tau), THEN microtubule dynamic instability will increase by ≥40% measured by EB3 comet tracking lifetime within 72 hours, AND stable
Predicted outcome: Dose-dependent increase in microtubule dynamics (shorter EB3 comet lifetimes, increased catastrophe frequency) and decrease in stable acetylated micro
Falsification: If microtubule dynamic parameters remain within ±15% of baseline despite >2-fold increase in MAP6 expression, the hypothesis is falsified
pendingconf 40%
IF MAPT-knockout neurons (which have low tau) are crossed with MAP6-knockout neurons to create a double knockout, THEN rescued expression of MAP6 at 3x endogenous levels will normalize axon branch dynamics to wildtype levels (within ±20%) within 5 days, whereas rescued MAP6 at 0.3x levels will fail
Predicted outcome: Rescue with high MAP6 restores dynamic remodeling rates to wildtype baseline; rescue with low MAP6 leaves dynamics elevated
Falsification: If both high and low MAP6 rescue conditions produce identical axon branch dynamics (within experimental noise), the ratio-dependent model 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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