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

Neurosci Lett. 1996 Jan 12;203(1):33-6. doi: 10.1016/0304-3940(95)12257-5.

Abstract

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.

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid beta-Protein Precursor / pharmacology*
  • Androstadienes / pharmacology
  • Animals
  • Cells, Cultured / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase / drug effects*
  • Hippocampus / drug effects*
  • Phosphotransferases / drug effects*
  • Rats
  • Wortmannin
  • tau Proteins / drug effects*

Substances

  • Amyloid beta-Protein Precursor
  • Androstadienes
  • Enzyme Inhibitors
  • tau Proteins
  • Glycogen Synthase
  • Phosphotransferases
  • Wortmannin