ACTIVATION OF TAU-PROTEIN KINASE-I GLYCOGEN SYNTHASE KINASE-3-BETA BYAMYLOID-BETA PEPTIDE-(25-35) ENHANCES PHOSPHORYLATION OF TAU IN HIPPOCAMPAL-NEURONS

According to the amyloid hypothesis for the pathogenesis of Alzheimer' s disease (AD), amyloid beta peptide (A beta) directly affects neurons , leading to neurodegeneration and tau phosphorylation, followed by th e production of paired helical filaments (PHF) in neurofibrillary tang les (NFT). To analyze the relationship between the phosphorylation sit es of tau and the activation of kinases in response to A beta, we trea ted cultured rat hippocampal neurons with a peptide fragment of A beta , A beta(25-35). A beta(25-35) treatment activated tau protein kinase I/glycogen synthase kinase-3 beta (TPK I/GSK-3 beta) but not glycogen synthase kinase-3 alpha (GSK-3 alpha) or mitogen activated protein kin ase (MAP kinase) in primary culture of hippocampal neurons. Using anti bodies that recognize phosphorylated sites of tau, we showed that tau phosphorylation was enhanced in at least five sites (Ser(199), Ser(202 ), Ser(396), Ser(404), and Ser(413) numbered according to the human ta u isoform containing 441 amino acid residues), to an extent that depen ded on the level of TPK I/GSK-3 beta. Treatment with TPK I/GSK-3 beta antisense oligonucleotide inhibited the enhancement of tau phosphoryla tion induced by A beta(25-35) exposure. Thus, TPK I/GSK-3 beta activat ion by A beta(25-35) may lead to extensive tau phosphorylation. (C) 19 98 Elsevier Science Ireland Ltd. All rights reserved.