TGF-ß1 protects against Aß-neurotoxicity via the phosphatidylinositol-3-kinase pathway

1. Neurobiol Dis. 2008 May;30(2):234-42.TGF-beta 1 protects against Abeta-neurotoxicity via thephosphatidylinositol-3-kinase pathway.Caraci F, Battaglia G, Busceti C, Biagioni F, Mastroiacovo F, Bosco P, Drago F,Nicoletti F, Sortino MA, Copani A.Department of Pharmaceutical Sciences, University of Catania, 95125, Catania,Italy. carafil@hotmail.combeta-Amyloid (A beta) injection into the rat dorsal hippocampus had a smallneurotoxic effect that was amplified by i.c.v. injection of SB431542, a selectiveinhibitor of transforming growth factor-beta (TGF-beta) receptor. This suggested that TGF-beta acts as a factor limiting A beta toxicity. We examined theneuroprotective activity of TGF-beta1 in pure cultures of rat cortical neuronschallenged with A beta. Neuronal death triggered by A beta is known to proceedalong an aberrant re-activation of the cell cycle, and involves late beta-catenindegradation and tau hyperphosphorylation. TGF-beta1 was equally protective whenadded either in combination with, or 6 h after A beta. Co-added TGF-beta1prevented A beta-induced cell cycle reactivation, whereas lately added TGF-beta1 had no effect on the cell cycle, but rescued the late beta-catenin degradationand tau hyperphosphorylation. The phosphatidylinositol-3-kinase (PI-3-K)inhibitor, LY294402, abrogated all effects. Thus, TGF-beta1 blocks the wholecascade of events leading to A beta neurotoxicity by activating the PI-3-Kpathway.