Activation of tau protein kinase I glycogen synthase kinase-3β by amyloid β 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 the production of paired helical filaments (PHF) in neurofibrillary tangles (NFT). To analyze the relationship between the phosphorylation sites of tau and the activation of kinases in response to A beta, we treated 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 kinase (MAP kinase) in primary culture of hippocampal neurons. Using antibodies 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 tau isoform containing 441 amino acid residues), to an extent that depended on the level of TPK I/GSK-3 beta. Treatment with TPK I/GSK-3 beta antisense oligonucleotide inhibited the enhancement of tau phosphorylation induced by A beta(25-35) exposure. Thus, TPK I/GSK-3 beta activation by A beta(25-35) may lead to extensive tau phosphorylation. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.