What molecular mechanisms enable HMW tau to propagate more rapidly than fibrillar tau across neural networks?

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Composite

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Novelty

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Mechanistic

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Druggability

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Priority

85%

Importance

92%

Tractability

75%

Market price

50%

Description

The study shows HMW tau promotes faster propagation to distal brain regions compared to fibrillar tau, despite similar seeding potency. The underlying mechanisms driving this enhanced trans-synaptic spreading remain unknown, limiting therapeutic targeting of tau propagation.

Gap type: unexplained_observation Source paper: Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau. (2023, Acta neuropathologica, PMID:37341831)

Resolution criteria

Resolved when HMW tau propagation advantage over fibrillar tau is attributed to defined uptake, trafficking, or release mechanisms. Required evidence: matched HMW and fibrillar tau preparations characterized by size/conformation, neuronal uptake and trans-synaptic transfer assays, receptor/endocytosis perturbation, in vivo spreading maps, and seeding-normalized comparisons. Closure requires showing which property of HMW tau increases network spread despite similar seeding potency.

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