Next, we compared the phosphorylation status of WT and 2P tau. The level of phosphorylation was assessed on sites Ser 202/Thr 205, Thr 231, Ser 396 and Thr 181, which were found highly phosphorylated on WT tau (see Fig. 5a). In contrast to the absence of effects for misfolding and aggregation, the 2P modification clearly affected the pattern of tau hyperphosphorylation. When compared to WT tau, phosphorylation was significantly decreased in the 2P tau group for all the residues analyzed, 7 months after vector injection (Fig. 5b,c). The effect of the 2P modification was particularly dramatic on the phosphorylation of Ser 202/Thr 205, which was almost completely suppressed (Fig. 5c). Moreover, histological analysis confirmed these findings. Indeed, the immunoreactivity for AT8 (phosphorylation at Ser 202/Thr 205) was nearly absent, whereas PHF1 immunoreactivity (phosphorylation at Ser 396/Ser 404) was partly decreased in the cortex of the mice overexpressing 2P tau, as compared to WT tau (Fig. 5b). Overall, the main effect of the 2P modification appears to be a significant decrease in the extent of human tau hyperphosphorylation.