In order to devise effective therapies, it is however important to identify critical steps in the gain of toxic functions of tau in neurons. Tau missorting, often associated with the compromised interaction of the protein with microtubules, is considered as an initial step in this process9. Several factors determine the affinity of different tau isoforms for microtubules, such as the number of repeats in the microtubule-binding domain (3 R versus 4 R), or the extent and site of tau phosphorylation. The phosphorylation-induced dissociation of tau from tubulin has been proposed to cause the loss of the microtubule-stabilizing function of tau, possibly contributing to neuronal degeneration10–12. When dissociated from microtubules, tau can then acquire various conformations, such as a compact “paperclip-like” conformation bringing together the N- and C-terminal portions of the protein13. Furthermore, the microtubule-binding domain contains hexapeptide motifs, which have a propensity to form β-sheets14. The transition to β-sheet structure is considered to be an important step, which promotes the formation of oligomers that can be competent for further aggregation into larger fibrillar structures such as PHF15. It is therefore important to determine how variations in the amino-acid sequence of the microtubule-binding domain critically control the kinetic of this process16–18.