Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression
Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression
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DOI：
10.1111/jnc.15184
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发表时间：
2020-09-30
影响因子：
4.7
通讯作者：
Chen, Guo-Jun
中科院分区：
文献类型：
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作者：
Li, Kun-Yi;Xiang, Xiao-Jiao;Chen, Guo-Jun
硫氧还蛋白-2(TXN_2)是一种线粒体蛋白，是一种内源性抗氧化酶。长期以来，线粒体功能障碍和氧化应激是阿尔茨海默病(AD)的发病机制之一。我们推测线粒体TXN_2可能在AD样病理中起作用。在本研究中，我们发现在稳定表达全长人淀粉样β前体蛋白(HEK-APP)的SH-SY5Y和HEK细胞中，TXN_2沉默或过度表达分别选择性地增加或降低β-位点淀粉样前体蛋白裂解酶1(BACE1)的转录，而不改变参与APP催化加工的其他酶的蛋白水平。结果，TXN_2显著降低了β-淀粉样蛋白(Aβ)水平。此外，在被3-硝基丙酸(3-NP)处理的细胞中，TXN_2沉默导致BACE1蛋白水平进一步增加，提示TXN_2在ROS清除中起作用。3-NP可增加ROS和促进线粒体功能障碍。下游信号可能涉及核因子kappaB，因为TXN2降低了p65和ikappa Bα的磷酸化，而p65基因敲除显著减弱了TXN2对BACE1的调节。同时，TXN_2沉默或过表达改变了细胞内ROS水平、细胞凋亡相关蛋白和细胞存活率。在阿尔茨海默病动物模型APPswe/PS1E9小鼠中，大脑皮质和海马区TXN2蛋白水平在12个月时下降，但在6个月时没有下降，表明这种下降是年龄依赖性的。总的来说，TXN2通过细胞内ROS和核因子kappaB信号调节BACE1的表达和淀粉样蛋白的发生。TXN_2可能成为AD早期干预的潜在靶点。
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-beta 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, beta-amyloid protein (A beta) 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 NF kappa B, as TXN2 reduced the phosphorylation of p65 and I kappa B alpha; 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 NF kappa B signaling. TXN2 might serve as a potential target especially for early intervention of AD.