Nanobodies engineered with pH-sensitive membrane fusion domains could selectively penetrate vesicles in acidic microenvironments around tau aggregates while remaining inactive in normal physiological pH environments.
Auto-built from this analysis's top knowledge-graph edges.
graph TD
phosphatidylserine_exposu["phosphatidylserine exposure"] -->|associated with| APOPTOSIS["APOPTOSIS"]
pH_sensitive_membrane_fus["pH-sensitive_membrane_fusion_domain"] -->|activates| acidic_microenvironment["acidic_microenvironment"]
phosphatidylserine_bindin["phosphatidylserine-binding_domain"] -->|binds| phosphatidylserine["phosphatidylserine"]
curvature_sensitive_cell_["curvature-sensitive_cell_penetrating_peptide"] -->|penetrates| curved_membranes["curved_membranes"]
ATP_depleted_environment["ATP-depleted_environment"] -->|enables| membrane_penetration["membrane_penetration"]
tau_protein["tau_protein"] -->|interacts with| phosphatidylserine_1["phosphatidylserine"]
tau_protein_2["tau_protein"] -->|induces| membrane_curvature["membrane_curvature"]
tau_aggregation["tau_aggregation"] -->|causes| pH_acidification["pH_acidification"]
tau_aggregation_3["tau_aggregation"] -->|disrupts| cholesterol_depletion["cholesterol_depletion"]
tau_conformational_change["tau_conformational_change"] -->|triggers| membrane_disruption["membrane_disruption"]
tau_aggregation_4["tau_aggregation"] -->|causes| ATP_depletion["ATP_depletion"]
tau_aggregation_5["tau_aggregation"] -->|disrupts| membrane_asymmetry["membrane_asymmetry"]
style phosphatidylserine_exposu fill:#4fc3f7,stroke:#333,color:#000
style APOPTOSIS fill:#ce93d8,stroke:#333,color:#000
style pH_sensitive_membrane_fus fill:#4fc3f7,stroke:#333,color:#000
style acidic_microenvironment fill:#4fc3f7,stroke:#333,color:#000
style phosphatidylserine_bindin fill:#4fc3f7,stroke:#333,color:#000
style phosphatidylserine fill:#4fc3f7,stroke:#333,color:#000
style curvature_sensitive_cell_ fill:#4fc3f7,stroke:#333,color:#000
style curved_membranes fill:#4fc3f7,stroke:#333,color:#000
style ATP_depleted_environment fill:#4fc3f7,stroke:#333,color:#000
style membrane_penetration fill:#4fc3f7,stroke:#333,color:#000
style tau_protein fill:#4fc3f7,stroke:#333,color:#000
style phosphatidylserine_1 fill:#4fc3f7,stroke:#333,color:#000
style tau_protein_2 fill:#4fc3f7,stroke:#333,color:#000
style membrane_curvature fill:#4fc3f7,stroke:#333,color:#000
style tau_aggregation fill:#4fc3f7,stroke:#333,color:#000
style pH_acidification fill:#4fc3f7,stroke:#333,color:#000
style tau_aggregation_3 fill:#4fc3f7,stroke:#333,color:#000
style cholesterol_depletion fill:#4fc3f7,stroke:#333,color:#000
style tau_conformational_change fill:#4fc3f7,stroke:#333,color:#000
style membrane_disruption fill:#4fc3f7,stroke:#333,color:#000
style tau_aggregation_4 fill:#4fc3f7,stroke:#333,color:#000
style ATP_depletion fill:#4fc3f7,stroke:#333,color:#000
style tau_aggregation_5 fill:#4fc3f7,stroke:#333,color:#000
style membrane_asymmetry fill:#4fc3f7,stroke:#333,color:#000No linked papers recorded for this hypothesis yet.
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.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we engineer nanobodies targeting MAPT with pH-sensitive membrane fusion domains THEN we will observe selective vesicular penetration at pH 6.0 versus no significant penetration at pH 7.4 within 48 | Mean fluorescence intensity of labeled nanobody inside vesicles will be ≥3-fold higher in pH 6.0 condition compared to pH 7.4 condition, as quantified by high-c | — no observation — | pending | 0.65 |
| IF pH-activated membrane fusion nanobodies selectively penetrate acidic tau aggregate vesicles THEN we will observe ≥30% reduction in Thioflavin T-positive tau aggregates after 72 hours of nanobody tr | Stereological count of Thioflavin T-positive tau inclusions in hippocampus will decrease by ≥30% in nanobody-treated 3xTG mice compared to vehicle-treated contr | — no observation — | pending | 0.55 |