Via a β-sheet breaker effect, the 2P modification reduces the propensity of the ΔK280 pro-aggregation variant to accumulate in the sarkosyl-insoluble fraction37. The proline residues therefore decrease the toxicity of 2P ΔK280 tau overexpressed in transgenic mice. In the context of WT 4R0N tau, which poorly aggregates in physiological conditions, the 2P modification does not have any apparent effect on the level of MC1-positive or insoluble tau. In the absence of any pro-aggregation mutation, the amount of tau present in these fractions remains low and may not solely depend on β-sheet formation. However, our results support the possibility of a higher interaction of 2P tau with microtubules, possibly facilitated by its low phosphorylation status and/or the presence of these proline residues in key regions of the microtubule-binding domain. This is supported by the observation made in primary cultures of cortical neurons that 2P tau prevents the formation of filopodia in neurites exposed to vinblastine, a microtubule-destabilizing agent. Furthermore, this result suggests that 2P tau may compete more effectively than WT tau with vinblastine, to occupy the tau-binding site at the interface between α- and β-tubulin heterodimers31. Therefore, the conformation of the microtubule-binding domain might be critical for the interaction of tau with microtubules38.