TGF-β1 protects against Aβ-neurotoxicity via the phosphatidylinositol-3-kinase pathway

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 AP toxicity. We examined the neuroprotective activity of TGF-beta 1 in pure cultures of rat cortical neurons challenged with AP. Neuronal death triggered by AP is known to proceed along an aberrant re-activation of the cell cycle, and involves late P-catenin degradation and tau hyperphosphorylation. TGF-beta 1 was equally protective when added either in combination with, or 6 h after A beta. Co-added TGF-beta 1 prevented A beta-induced cell cycle reactivation, whereas lately added TGF-beta 1 had no effect on the cell cycle, but rescued the late P-catenin degradation and tau hyperphosphorylation. The phosphatidylinositol-3-kinase (PI-3-K) inhibitor, LY294402, abrogated all effects. Thus, TGF-beta 1 blocks the whole cascade of events leading to AP neurotoxicity by activating the PI-3-K pathway. (c) 2008 Elsevier Inc. All rights reserved.