Tau carrying the FTDP-17-associated P301S mutation has clearly different properties. In contrast to WT tau, the total level of the P301S mutant protein increases over time, indicating an effect of the mutation on tau turnover, possibly via accumulation of insoluble forms of the protein with a longer half-life42. Indeed, P301S tau displays enhanced propensity to aggregate, as demonstrated by the constant accumulation of MC1-immunoreactive tau species, and the formation of tau multimers. However, P301S tau appears to be proportionally less phosphorylated than WT tau. The only exception is the increased immunoreactivity for AT100, a phosphorylated tau epitope present at late stages of aggregation characterized by the presence of PHF. Remarkably, and in contrast to WT tau, the behavioral deficits induced by overexpression of P301S tau clearly progress as a function of age. This effect correlates with the increase in the amount of misfolded aggregated tau. The pathogenic effects of P301S tau are also underlined by the axonal damage observed in vivo (Fig. 4c), and by the neuritic swellings induced in cortical neurons exposed to vinblastine (Fig. 7d).