PHOSPHORYLATION OF MICROTUBULE-ASSOCIATED PROTEIN-TAU ON SER-262 BY AN EMBRYONIC 100 KDA PROTEIN-KINASE

This study examined the phosphorylation of tan on Ser 262, within the first microtubule-binding domain, by a developmentally regulated 100 k Da protein kinase exhibiting significantly greater activity in the emb ryonic rat brain than in the adult rat brain. This protein kinase co-p urified with microtubules and co-immunoprecipitated with both tau and MAP-2. In addition to phosphorylating tau, MAP-2, and a Ser 262-contai ning peptide, the present protein kinase activity was shown to autopho sphorylate as determined by the in-gel kinase assay in the absence of any protein or peptide polymerized into the matrix. Phosphorylation of tau with this protein kinase significantly reduced the tau-microtubul e interaction, and the effect was significantly greater with microtubu le-associated protein (MAP) preparations from embryonic brain than wit h preparations from the adult. Ser 262 is phosphorylated extensively i n paired helical filament (PHF) tau from Alzheimer's disease (AD) brai n, to a lesser extent in fetal tau, and only to a very minor extent in biopsy-derived human tau. Because the 100 kDa protein kinase activity phosphorylates Ser 262 and is higher in the fetal brain than the adul t brain, it is hypothesized that an inappropriate re-expression and/or re-activation of this or a similar developmentally regulated protein kinase could contribute to the phosphorylation of Ser 262 in PHF-tau, and thus play a role in the pathogenesis of AD. (C) 1997 Elsevier Scie nce B.V.