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β-Amyloid (Aβ) 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-β (TGF-β) receptor. This suggested that TGF-β acts as a factor limiting Aβ toxicity. We examined the neuroprotective activity of TGF-β1 in pure cultures of rat cortical neurons challenged with Aβ. Neuronal death triggered by Aβ is known to proceed along an aberrant re-activation of the cell cycle, and involves late β-catenin degradation and tau hyperphosphorylation. TGF-β1 was equally protective when added either in combination with, or 6 h after Aβ. Co-added TGF-β1 prevented Aβ-induced cell cycle reactivation, whereas lately added TGF-β1 had no effect on the cell cycle, but rescued the late β-catenin degradation and tau hyperphosphorylation. The phosphatidylinositol-3-kinase (PI-3-K) inhibitor, LY294402, abrogated all effects. Thus, TGF-β1 blocks the whole cascade of events leading to Aβ neurotoxicity by activating the PI-3-K pathway.