Caraci Filippo, Battaglia Giuseppe, Busceti Carla, Biagioni Francesca, Mastroiacovo Federica, Bosco Paolo, Drago Filippo, Nicoletti Ferdinando, Sortino Maria Angela, Copani Agata
Department of Pharmaceutical Sciences, University of Catania, 95125, Catania, Italy.
Neurobiol Dis. 2008 May;30(2):234-42. doi: 10.1016/j.nbd.2008.01.007. Epub 2008 Feb 13.
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.
向大鼠背侧海马体注射β-淀粉样蛋白（Aβ）会产生轻微的神经毒性作用，而通过脑室内注射SB431542（一种转化生长因子-β（TGF-β）受体的选择性抑制剂）可增强这种作用。这表明TGF-β作为一种限制Aβ毒性的因子。我们检测了TGF-β1在受到Aβ攻击的大鼠皮层神经元纯培养物中的神经保护活性。已知由Aβ引发的神经元死亡是沿着细胞周期的异常重新激活进行的，并且涉及晚期β-连环蛋白降解和tau蛋白过度磷酸化。当与Aβ联合添加或在Aβ添加6小时后添加时，TGF-β1具有同等的保护作用。联合添加的TGF-β1可防止Aβ诱导的细胞周期重新激活，而后期添加的TGF-β1对细胞周期没有影响，但可挽救晚期β-连环蛋白降解和tau蛋白过度磷酸化。磷脂酰肌醇-3-激酶（PI-3-K）抑制剂LY294402消除了所有作用。因此，TGF-β1通过激活PI-3-K途径阻断了导致Aβ神经毒性的整个事件级联反应。
