ID: h-a0c62d04e6
Hypothesis
BIN1-dependent trafficking defects determine whether post-Aβ tau missorting resolves or persists
Aβ initially perturbs tau localization, but persistence depends on BIN1-regulated membrane and endocytic trafficking that prevents tau re-entry into the axon and stabilizes dendritic retention.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 6 support✗ 2 oppose
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🧪 Overview
Aβ initially perturbs tau localization, but persistence depends on BIN1-regulated membrane and endocytic trafficking that prevents tau re-entry into the axon and stabilizes dendritic retention. This is a useful genetic-modifier hypothesis, but currently the least supported as a primary mechanism.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["A beta<br/>Perturbation"]
B["BIN1 Membrane<br/>Trafficking Defects"]
C["Tau Axonal<br/>Re-entry Blocked"]
D["Dendritic<br/>Retention Stabilized"]
E["Tau Missorting<br/>Persistence"]
F["Tau Missorting<br/>Resolution"]
A --> B
B --> C
B --> D
C --> E
D --> F
E --> F
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7⚖️ Evidence
⚖️ Evidence Matrix6 supports2 contradicts
Supports
BIN1 is a strong AD risk locus with links to tau biology and trafficking, supporting modifier-level relevance.
Supports
BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes.
Supports
Bend it like BIN1: how a membrane-curving adaptor protein shapes cardiac physiology.
Contradicts
The BIN1-tau relationship is complex and not straightforward, with sparse evidence that BIN1 controls post-Aβ persistence of missorting specifically.
Contradicts
Isoform- and cell-type-specific BIN1 biology makes simple causal interpretations in iPSC neurons uncertain.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — BIN1
No curated PDB or AlphaFold mapping for BIN1 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for BIN1,MAPT from GTEx v10.
💉 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 BIN1,MAPT.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF BIN1 is knocked down in human iPSC-derived neurons prior to Aβ42 oligomer exposure (100 nM, 6 hours), THEN tau will exhibit persistent dendritic and somatic accumulation rather than returning to ax | Tau will remain mislocalized (pTau fluorescence intensity in dendrites >2x baseline, axonal/axonal initial segment intensity <50% baseline) at both 48 and 72 ho | — no observation — | pending | 0.35 |
| IF BIN1 endocytic trafficking function is selectively enhanced via overexpression of the BIN1 long isoform with intact BAR domain (BIN1-001, NP_008905.3) in 5xFAD mice at 6 months of age, THEN the pro | Somatodendritic tau accumulation (measured by AT8+ or MC1+ immunoreactivity confined to soma and dendrites) will be present in ≥60% of CA1 neurons in 5xFAD/GFP | — no observation — | pending | 0.28 |
🔮 Falsifiable Predictions (2)
pendingconf 35%
IF BIN1 is knocked down in human iPSC-derived neurons prior to Aβ42 oligomer exposure (100 nM, 6 hours), THEN tau will exhibit persistent dendritic and somatic accumulation rather than returning to axonal localization within 72 hours post-Aβ washout, compared to neurons treated with non-targeting si
Predicted outcome: Tau will remain mislocalized (pTau fluorescence intensity in dendrites >2x baseline, axonal/axonal initial segment intensity <50% baseline) at both 48
Falsification: If tau localization resolves normally in both BIN1 knockdown and control conditions (no significant difference in axonal/dendritic tau ratio at 48 or 72 hours post-washout, p>0.05 by ANOVA with Bonfer
pendingconf 28%
IF BIN1 endocytic trafficking function is selectively enhanced via overexpression of the BIN1 long isoform with intact BAR domain (BIN1-001, NP_008905.3) in 5xFAD mice at 6 months of age, THEN the proportion of hippocampal CA1 neurons displaying pathological tau missorting into somatodendritic compa
Predicted outcome: Somatodendritic tau accumulation (measured by AT8+ or MC1+ immunoreactivity confined to soma and dendrites) will be present in ≥60% of CA1 neurons in
Falsification: If the percentage of CA1 neurons with somatodendritic tau accumulation does not differ significantly between BIN1-overexpressing and GFP-control 5xFAD mice (<20% difference, p>0.05 by chi-square test)
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _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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