ID: h-86101c8cd6ec
Hypothesis
Developmental stage-specific dominance of tau vs MAP6 function
During early development, tau predominates to maximize plasticity and rapid axon extension; as maturation proceeds, MAP6 increasingly dominates to establish long-term stability.
EvidenceModerate (50%)📖 6 cit🗣 1 debates✓ 6 support✗ 2 oppose
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🧪 Overview
During early development, tau predominates to maximize plasticity and rapid axon extension; as maturation proceeds, MAP6 increasingly dominates to establish long-term stability
Prediction: The tau:MAP6 ratio on microtubules shifts progressively during development, with temporal coincidence of domain segregation correlating with developmental transitions
🧬 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 supports2 contradicts
Supports
During early development, tau predominates to maximize plasticity and rapid axon extension; as maturation proceeds, MAP6 increasingly dominates to establish long-term stability
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.
Contradicts
Tau/MAP6 antagonism is shown in neuronal development models, but this does not establish that the same balance drives adult neurodegeneration progression or treatment response.
Contradicts
A microtubule-stabilizing peptide strategy failed to show clinical benefit in progressive supranuclear palsy, cautioning against simple cytoskeletal-stabilization translation in tauopathy.
📖 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: 65%
0
Active
Active
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Completed
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Total Enrolled
Total Enrolled
PHASE1
Highest Phase
Highest Phase
COMPLETED·NCT03718494 · Mayo Clinic
Alzheimer Dementia
Brain Magnetic Resonance Imaging (MRI) F-18 Florbetapir Positron Emission Tomography (PET) Imaging F-18 AV-1451 Positron Emission Tomography (PET) Imaging
TERMINATED·NCT02406027 · Janssen Research & Development, LLC
Alzheimer Disease
JNJ-54861911, 10 mg JNJ-54861911, 25 mg Placebo
COMPLETED·NCT06224920 · Ludwig-Maximilians - University of Munich
Alzheimer Disease Corticobasal Syndrome
magnetic resonance imaging electroencephalography blood and CSF biomarker
COMPLETED·NCT05423522 · Medesis Pharma SA
Alzheimer's Disease
NanoLithium® NP03 Placebo
UNKNOWN·NCT04248270 · Chang Gung Memorial Hospital
Alzheimer's Disease Vascular Dementia Dementia
18F-PM-PBB3
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.
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📊 Market Indicators
7d Trend
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7d Momentum
▼ 0.2%
Volatility
Medium
0.0307
Events (7d)
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Price History
▲0.5%💾 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 we measure tau and MAP6 protein levels on assembled microtubules across postnatal development in mice (E18, P7, P14, P30, P90), THEN the tau:MAP6 ratio on microtubules will decrease progressively b | Progressive decrease in tau:MAP6 ratio on microtubule fraction; tau levels decline while MAP6 levels increase | — no observation — | pending | 0.70 |
| IF we perform tau knockdown in cultured hippocampal neurons derived from early postnatal mice (P0-P2) versus mature mice (P21-P28), THEN overexpression of MAP6 will fully rescue axon extension defects | At P0-P2 neurons: tau rescue >80% of control axon length, MAP6 rescue <40%. At P21-P28 neurons: MAP6 rescue >80% of control axon length, tau rescue <40% | — no observation — | pending | 0.65 |
🔮 Falsifiable Predictions (2)
pendingconf 70%
IF we measure tau and MAP6 protein levels on assembled microtubules across postnatal development in mice (E18, P7, P14, P30, P90), THEN the tau:MAP6 ratio on microtubules will decrease progressively by approximately 50-70% from early (E18-P7) to mature (P30-P90) stages.
Predicted outcome: Progressive decrease in tau:MAP6 ratio on microtubule fraction; tau levels decline while MAP6 levels increase
Falsification: The tau:MAP6 ratio remains constant or increases during development, contradicting the predicted shift toward MAP6 dominance
pendingconf 65%
IF we perform tau knockdown in cultured hippocampal neurons derived from early postnatal mice (P0-P2) versus mature mice (P21-P28), THEN overexpression of MAP6 will fully rescue axon extension defects in mature neurons but only partially in early neurons, while tau overexpression will show the oppos
Predicted outcome: At P0-P2 neurons: tau rescue >80% of control axon length, MAP6 rescue <40%. At P21-P28 neurons: MAP6 rescue >80% of control axon length, tau rescue <4
Falsification: Both tau and MAP6 rescue axon extension equally at both developmental stages, indicating functional redundancy without temporal specificity
▸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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