Fig. 5: Polymorphism of ex vivo derived tau fibrils traces back to the innate structural features of PAM4 fibrils.

The PAM4 folds recovered in isolation match its conformation in patient-derived tau amyloid fibril structures belonging to each branch of their previously proposed structural classification¹⁴, including 3R, 4R and 3R/4R isoforms. Structural alignments reveal that the PAM4 FoldC matches the AD conformation and shows reasonable fit to CTE (3R/4R), as shown by their respective RMSD calculations (1.43 Å and 1.63 Å, respectively). Similarly, FoldB matches the PSP conformation and shows a mismatch at the C-terminal of the region in the PiD conformation, respectively (RMSD values of 0.53 Å and 1.69 Å). Finally, FoldD perfectly overlaps the CBD and AGD (4 R) conformations (RMSD values of 1.19 Å and 1.06 Å, respectively). Zoom-in inlets highlight the superposed PAM4 segments from tau polymorphs and the individual folds observed in isolation using cryoEM. Tau structures are coloured in grey, whereas individual PAM4 folds are coloured as in Fig. 4d.