The pathology observed in the adult mice overexpressing each of the three variants of the 4R0N tau protein is summarized in Fig. 8. Remarkably, hyperphosphorylation is most prevalent on the WT form of tau, and appears to be reduced when proline residues are introduced in the microtubule-binding region of the tau protein (2P tau), or in presence of the pathogenic P301S mutation. In particular, the residues Ser396 (PHF1 epitope), Ser202/Thr 205 (AT8 epitope), Thr 181 (the most frequent phosphorylation site measured in clinical AD samples) and Thr 231 are more heavily phosphorylated on WT tau than on P301S and 2P tau. Notably, phosphorylation of Thr 231 can promote the dissociation of the tau protein form microtubules, via conformational changes induced by trans-to-cis isomerization36. P301S and 2P mutations in the microtubule-binding region reduce the propensity of the protein to become hyperphosphorylated and are therefore likely to facilitate tau interaction with microtubules, as suggested by the effect of 2P and P301S tau on microtubule bundling in vivo.Figure 8Motifs in the tau microtubule-binding domain affect the development of the tau pathology in vivo. Schematic representation of the pathology observed in the mouse forebrain following overexpression of each tau variant. Background colors represent the relative abundance and arrows indicate possible transitions between the different states.