Overall, these results indicate that in presence of vinblastine, cortical neurons overexpressing either WT or P301S tau develop signs of microtubule severing and axonal damage including formation of filopodia (WT and P301S tau) and neuritic swellings (P301S tau). These effects are significantly decreased in neurons overexpressing 2P tau. The insertion of β-sheet breaking proline residues in regions flanking the second microtubule-binding repeat enhances the ability of tau to stabilize microtubules, most likely by increasing the ability of tau to compete with vinblastine for microtubule binding.