TGF-beta 1 protects against Abeta-neurotoxicity via the phosphatidylinositol-3-kinase pathway |
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Authors: | Caraci Filippo Battaglia Giuseppe Busceti Carla Biagioni Francesca Mastroiacovo Federica Bosco Paolo Drago Filippo Nicoletti Ferdinando Sortino Maria Angela Copani Agata |
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Institution: | Department of Pharmaceutical Sciences, University of Catania, 95125, Catania, Italy. carafil@hotmail.com |
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Abstract: | beta-Amyloid (A beta) injection into the rat dorsal hippocampus had a small neurotoxic effect that was amplified by i.c.v. injection of SB431542, a selective inhibitor of transforming growth factor-beta (TGF-beta) receptor. This suggested that TGF-beta acts as a factor limiting A beta toxicity. We examined the neuroprotective activity of TGF-beta1 in pure cultures of rat cortical neurons challenged with A beta. Neuronal death triggered by A beta is known to proceed along an aberrant re-activation of the cell cycle, and involves late beta-catenin degradation and tau hyperphosphorylation. TGF-beta1 was equally protective when added either in combination with, or 6 h after A beta. Co-added TGF-beta1 prevented A beta-induced cell cycle reactivation, whereas lately added TGF-beta1 had no effect on the cell cycle, but rescued the late beta-catenin degradation and tau hyperphosphorylation. The phosphatidylinositol-3-kinase (PI-3-K) inhibitor, LY294402, abrogated all effects. Thus, TGF-beta1 blocks the whole cascade of events leading to A beta neurotoxicity by activating the PI-3-K pathway. |
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