Seed-competent tau conformers in trans-synaptic spread

#1

Repeat-domain exposure defines seed-competent tau conformers

Tau assemblies become seed-competent when their repeat-domain surfaces adopt a conformation that both survives transfer and templates monomeric tau into pathological aggregates. This conformer-specific templating mechanism, supported by structural studies of disease-specific tau filaments, suggests that the exposed repeat domain interface is the critical determinant distinguishing pathogenic from non-pathogenic tau conformations. Non-pathogenic transferred tau lacks this exposed templating inter...

Tau assemblies become seed-competent when their repeat-domain surfaces adopt a conformation that both survives transfer and templates monomeric tau into pathological aggregates. This conformer-specific templating mechanism, supported by structural studies of disease-specific tau filaments, suggests that the exposed repeat domain interface is the critical determinant distinguishing pathogenic from non-pathogenic tau conformations. Non-pathogenic transferred tau lacks this exposed templating interface despite similar uptake, indicating that cellular internalization alone is insufficient for prion-like propagation. The probabilistic model of Alzheimer disease revised in 2022 suggests that such templated aggregation processes may be central to disease progression. Conformational exposure of the repeat domain thus defines seed-competent tau conformers and may represent a therapeutic target for preventing the establishment of the templating interface required for neurodegeneration.

#2

A tau PTM barcode gates trans-synaptic templating

Specific combinations of tau phosphorylation, acetylation, and truncation mark assemblies that evade degradation and template after synaptic transfer. Altering the PTM barcode should convert seed-competent tau into transferable but weakly pathogenic tau.

#3

Endosomal escape determines whether transferred tau becomes pathogenic

Some tau species are transferred between neurons but remain non-pathogenic because they stay trapped in degradative endosomal routes. Seed-competent tau either escapes into cytosol or traffics through compartments that expose it to soluble tau substrate.