Tau protein can be transformed into an Alzheimer-like state by phosphorylation with a kinase activity from brain [Biernat et al. (1992) EMBO J. 11, 1593–1597]. Here we show that the phosphorylation at Ser-Pro motifs strongly decreases tau's affinity for Microtubules. The major reduction occurs during the first of the three main stages of phosphorylation. The data explain the lower Stability of microtubules resulting from the pathological tau phosphorylation.
