The switch of tau protein to an Alzheimer‐like state includes the phosphorylation of two serine‐proline motifs upstream of the microtubule binding region

The paired helical filaments (PHFs) of Alzheimer's disease consist mainly of the microtubule‐associated protein tau. PHF tau differs from normal human brain tau in that it has a higher Mr and a special state of phosphorylation. However, the protein kinase(s) involved, the phosphorylation sites on tau and the resulting conformational changes are only poorly understood. Here we show that a new monoclonal antibody, AT8, records the PHF‐like state of tau in vitro, and we describe a kinase activity that turns normal tau into a PHF‐like state. The epitope of AT8 is around residue 200, outside the region of internal repeats and requires the phosphorylation of serines 199 and/or 202. Both of these are followed by a proline, suggesting that the kinase activity belongs to the family of proline‐directed kinases. The epitope of AT8 is nearly coincident with that of another phosphorylation‐dependent antibody, TAU1 [Binder, L.I., Frankfurter, A. and Rebhun, L. (1985) J. Cell Biol., 101, 1371–1378], but the two are complementary since TAU1 requires a dephosphorylated epitope.