What are the mechanisms of tau vesicle trafficking and surface accessibility for therapeutic targeting?

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50%

Description

The debate highlighted uncertainty about whether pathological tau in vesicles is surface-accessible or intracellular. This determines feasibility of extracellular targeting approaches and drug delivery requirements.

Source: Debate session sess_SDA-2026-04-10-SDA-2026-04-09-gap-debate-20260409-201742-d279750b (Analysis: SDA-2026-04-09-gap-debate-20260409-201742-d279750b)

Resolution criteria

Gap closes when: (1) Cryo-electron tomography or super-resolution imaging of tau-containing vesicles in patient-derived neurons directly visualizes tau topology (luminal vs. surface-exposed) with >= 90% of vesicle population characterized; and (2) a cell-surface biotinylation assay quantifies the fraction of tau accessible to extracellular antibodies on intact cells; and (3) endocytosis inhibitors (dynasore or Pitstop) demonstrate >= 50% reduction in tau uptake only when tau is surface-accessible. Deliverable: structural imaging dataset with quantified topology fractions and uptake inhibition data.

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