Salins Pradeep, He Yang, Olson Kelly, Glazner Gordon, Kashour Tarek, Amara Francis
Department of Biochemistry and Medical Genetics, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, MB R3E 0W3 Canada.
Neurosci Lett. 2008 Jan 3;430(1):81-6. doi: 10.1016/j.neulet.2007.10.025. Epub 2007 Oct 30.
Alzheimer's disease (AD) is a neurodegenerative disorder, due to excess amyloid-beta peptide (Abeta). TGF-beta1 and beta-catenin signaling pathways have been separately implicated in modulating Abeta-neurotoxicity. However, the underlying mechanisms remain unclear. Here, we report that TGF-beta1 and nuclear Smad7 and beta-catenin levels were markedly upregulated in cortical brain regions of the TgCRND8 mice, a mouse model of familial Alzheimer's disease. Coimmunoprecipitation of cortical brain tissue lysates revealed an interaction between Smad7 and beta-catenin. This interaction which was significantly enhanced in the TgCRND8 mice was also associated with an increase in TCF/LEF DNA-shift binding activity. TCF/LEF reporter gene activity was significantly increased in mouse primary cortical neuronal cultures (MCN) from the TgCRND8 mice, compared to controls. Interestingly, exposure of MCN to Abeta(1-42) led to an increase in TGF-beta1 and nuclear levels of both beta-catenin and Smad7. Furthermore, addition of TGF-beta1 to the MCN caused an increase in apoptosis and Smad7 levels. When Smad7 or beta-catenin levels were reduced by siRNA, TGF-beta1-induced apoptosis was suppressed, indicating that both Smad7 and beta-catenin are required for TGF-beta1-induced neurotoxicity. Since Abeta(1-42)-induced TGF-beta1, we suggest that TGF-beta1 may amplify Abeta(1-42)-mediated neurodegeneration in AD via Smad7 and beta-catenin interaction and nuclear localization.
阿尔茨海默病（AD）是一种神经退行性疾病，由过量的β-淀粉样肽（Aβ）引起。转化生长因子β1（TGF-β1）和β-连环蛋白信号通路分别与调节Aβ神经毒性有关。然而，其潜在机制仍不清楚。在此，我们报告在家族性阿尔茨海默病小鼠模型TgCRND8的大脑皮质区域中，TGF-β1、核内Smad7和β-连环蛋白水平显著上调。大脑皮质组织裂解物的免疫共沉淀显示Smad7与β-连环蛋白之间存在相互作用。这种相互作用在TgCRND8小鼠中显著增强，也与TCF/LEF DNA迁移结合活性的增加有关。与对照组相比，来自TgCRND8小鼠的小鼠原代皮质神经元培养物（MCN）中TCF/LEF报告基因活性显著增加。有趣的是，将MCN暴露于Aβ（1-42）会导致TGF-β1以及β-连环蛋白和Smad7核水平的增加。此外，向MCN中添加TGF-β1会导致细胞凋亡和Smad7水平增加。当通过小干扰RNA（siRNA）降低Smad7或β-连环蛋白水平时，TGF-β1诱导的细胞凋亡受到抑制，表明Smad7和β-连环蛋白都是TGF-β1诱导神经毒性所必需的。由于Aβ（1-42）可诱导TGF-β1，我们认为TGF-β1可能通过Smad7和β-连环蛋白的相互作用及核定位来放大Aβ（1-42）介导的阿尔茨海默病神经退行性变。
