A Small Tau Fragment Specifically Templates Four Repeat Tau Aggregates Through Multiple Generations.

Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. We used a 19-residue probe peptide spanning the R2/R3 splice junction of tau to induce aggregation specifically of 4R, but not 3R tau. The aggregates can propagate as isoform-specific seeds over multiple generations, have a high β-sheet content, a lipid signal, and resemble the PSP cryo-EM fold. A simulation of peptide free energy landscapes pinpointed the features of the hairpin structure uniquely found in the cryo-EM structures of pure 4R tauopathies and captured in the peptide. These molecular dynamic simulations were experimentally validated by the S305K substitution in 4R tau, corresponding to the position found in 3R tau. This single amino acid substitution prevented tau aggregates induced by the prion-like probe peptide. The tau aggregates were dynamic and displayed growth, stability, and shrinking over time. These results could serve as the basis for tau isoform-specific therapeutic interventions.