Exposure of rat hippocampal neurons to amyloid beta peptide (25-35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 beta.
Exposure of rat hippocampal neurons to the peptide amyloid beta (A beta) (25-35) as well as A beta (1-40) peptides enhances phosphorylation of tau to a paired helical filament (PHF)-state through activation of tau protein kinase I (TPK I)/glycogen synthase kinase-3 beta (GSK-3 beta) [Busciglio, J., Lorenzo, A., Yeh, J. and Yankner, B.A., Neuron, 14 (1995) 879-888; Takashima, A., Ishiguro, K., Noguchi, K., Michel, G., Hoshi, M., Sato, K., Takahashi, M., Hoshino, T., Uchida, T. and Imahori, K., Neurosci. Meeting Abstr., 671 (1995) 17]. In order to examine the effects of A beta treatment on intracellular signaling mechanism, we have investigated the role of phosphatidyl inositol-3 (PI-3) kinase in the phosphorylation of tau. A beta (25-35) exposure induced an inactivation of PI-3 kinase and an activation of TPK I/GSK-3 beta in rat hippocampal culture. Wortmannin, an inhibitor of PI-3 kinase, also activated TPK I/GSK-3 beta, leading to an enhancement of tau phosphorylation and neuronal death in hippocampal culture. These results suggest that A beta (25-35) inhibition of PI-3 kinase results in the activation of TPK I/GSK-3 beta, the phosphorylation of tau, and resultant neuronal death in rat hippocampal neurons.
Takashima
A
A
Mitubishi Kasei Institute of Life Sciences, Tokyo, Japan.
Noguchi
K
K
Michel
G
G
Mercken
M
M
Hoshi
M
M
Ishiguro
K
K
Imahori
K
K
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006006:Glycogen Synthase / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D010770:Phosphotransferases / Q000187:drug effects*; D051381:Rats; D000077191:Wortmannin; D016875:tau Proteins / Q000187:drug effects*
D016564:Amyloid beta-Protein Precursor; D000730:Androstadienes; D004791:Enzyme Inhibitors; D016875:tau Proteins; D006006:Glycogen Synthase; D010770:Phosphotransferases; D000077191:Wortmannin