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 bet a) (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 be ta) [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., Sate, K., Takahashi, M., Hoshino, T., Uchida, T. and Imaho ri, 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 ina ctivation 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 act ivated TPK I/GSK-3 beta, leading to an enhancement of tau phosphorylat ion and neuronal death in hippocampal culture. These results suggest t hat 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 neuron al death in rat hippocampal neurons.