Thioredoxin-2 (TXN2) is a mitochondrial protein and represents one of the intrinsic antioxidant enzymes. It has long been recognized that mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of Alzheimer's disease (AD). We hypothesized that mitochondrial TXN2 might play a role in AD-like pathology. In this study, we found that in SH-SY5Y and HEK cells stably express full-length human amyloid-β precursor protein (HEK-APP), TXN2 silencing or over-expression selectively increased or decreased the transcription of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), respectively, without altering the protein levels of others enzymes involved in the catalytic processing of APP. As a result, β-amyloid protein (Aβ) levels were significantly decreased by TXN2. In addition, in cells treated with 3-nitropropionic acid (3-NP) that is known to increase reactive oxygen species (ROS) and promote mitochondrial dysfunction, TXN2 silencing resulted in further enhancement of BACE1 protein levels, suggesting a role of TXN2 in ROS removal. The downstream signaling might involve NFκB, as TXN2 reduced the phosphorylation of p65 and IκBα; and p65 knockdown significantly attenuated TXN2-mediated regulation of BACE1. Concomitantly, the levels of cellular ROS, apoptosis-related proteins and cell viability were altered by TXN2 silencing or over-expression. In APPswe/PS1E9 mice, an animal model of AD, the cortical and hippocampal TXN2 protein levels were decreased at 12 months but not at 6 months, suggesting an age-dependent decline. Collectively, TXN2 regulated BACE1 expression and amyloidogenesis via cellular ROS and NFκB signaling. TXN2 might serve as a potential target especially for early intervention of AD.

中文翻译：

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线粒体TXN2通过选择性抑制BACE1表达来减弱淀粉样蛋白生成

硫氧还蛋白2（TXN2）是一种线粒体蛋白，代表固有的抗氧化酶之一。长期以来，人们已经认识到线粒体功能障碍和氧化应激是阿尔茨海默氏病（AD）的发病机理。我们假设线粒体TXN2可能在AD样病理中起作用。在这项研究中，我们发现在SH-SY5Y和HEK细胞中稳定表达全长人类淀粉样β前体蛋白（HEK-APP），TXN2沉默或过表达选择性增加或减少了β-位淀粉样前体蛋白的转录。分别裂解酶1（BACE1），而不会改变APP催化过程中涉及的其他酶的蛋白质水平。结果，TXN2显着降低了β-淀粉样蛋白（Aβ）水平。此外，在用3-硝基丙酸（3-NP）处理的细胞中，已知该活性会增加活性氧（ROS）并促进线粒体功能障碍，TXN2沉默导致BACE1蛋白水平进一步提高，表明TXN2在ROS去除中的作用。下游信号可能涉及NFκB，因为TXN2降低了p65和IκBα的磷酸化。p65敲低显着减弱了TXN2介导的BACE1调控。同时，TXN2沉默或过表达改变了细胞ROS，细胞凋亡相关蛋白和细胞活力的水平。在ADswe / PS1E9小鼠（AD的动物模型）中，皮质和海马TXN2蛋白水平在12个月时下降，但在6个月时没有下降，表明年龄依赖性下降。总体而言，TXN2通过细胞ROS和NFκB信号传导调节BACE1表达和淀粉样蛋白生成。