Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid 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 (Abeta) 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 Abeta, we treated cultured rat hippocampal neurons with a peptide fragment of Abeta, Abeta(25-35). Abeta(25-35) treatment activated tau protein kinase I/glycogen synthase kinase-3beta (TPKI/GSK-3beta) but not glycogen synthase kinase-3alpha (GSK-3alpha) 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 (Ser199, Ser202, Ser396, Ser404, and Ser413 numbered according to the human tau isoform containing 441 amino acid residues), to an extent that depended on the level of TPK I/GSK-3beta. Treatment with TPK I/GSK-3beta antisense oligonucleotide inhibited the enhancement of tau phosphorylation induced by Abeta(25-35) exposure. Thus, TPK I/GSK-3beta activation by Abeta(25-35) may lead to extensive tau phosphorylation.
Takashima
A
A
Mitsubishi Kasei Institute of Life Sciences, Tokyo, Japan. kenneth@brain.riken.go.jp
Honda
T
T
Yasutake
K
K
Michel
G
G
Murayama
O
O
Murayama
M
M
Ishiguro
K
K
Yamaguchi
H
H
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016375:Antisense Elements (Genetics); D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006624:Hippocampus / Q000166:cytology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000906:Antibodies; D016375:Antisense Elements (Genetics); D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D016875:tau Proteins; D038341:Glycogen Synthase Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase