STRESS-ACTIVATED PROTEIN KINASE C-JUN N-TERMINAL KINASE PHOSPHORYLATES TAU-PROTEIN/

A proportion of the neuronal microlubule-associated protein (MAP) tau is highly phosphorylated in foetal and adult brain, whereas the majori ty of tau in the neurofibrillary tangles of Alzheimer's patients is hy perphosphorylated; many of the phosphorylation sites are serines or th reonines followed by prolines. Several kinases phosphorylate tau at su ch sites in vitro, We have now shown that purified recombinant stress- activated protein kinase/c-Jun N-terminal kinase, a proline-directed k inase of the MAP kinase extended family, phosphorylates recombinant ta u in vitro on threonine and serine residues. Western blots using antib odies to phosphorylation-dependent tau epitopes demonstrated that phos phorylation occurs in both of the main phosphorylated regions of tau p rotein. Unlike glycogen synthase kinase-3, the c-Jun N-terminal kinase readily phosphorylates Thr(205) and Ser(422), which are more highly p hosphorylated in Alzheimer tau than in foetal or adult tau. Glycogen s ynthase kinase-3 may preferentially phosphorylate the sites found phys iologically, in foetal and to a smaller extent in adult tau, whereas s tress activated/c-Jun N-terminal kinase and/or other members of the ex tended MAP kinase family may be responsible for pathological proline-d irected phosphorylations. Inflammatory processes in Alzheimer brain mi ght therefore contribute directly to the pathological formation of the hyperphosphorylated tau found in neurofibrillary tangles.