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The role of ceramide and SEW 2871 in the transcription of enzymes involved in amyloid b precursor protein metabolism in an experimental model of Alzheimer's disease.
Folia Neuropathologica ( IF 2 ) Pub Date : 2018-12-05 , DOI: 10.5114/fn.2018.78700
Kinga Czubowicz , Sylwia Wójtowicz , Przemysław Leonard Wencel , Robert Piotr Strosznajder

Alzheimer's disease (AD) is characterized by alterations of amyloid precursor protein (APP) metabolism, accumulation of amyloid  peptides (A), hyperphosphorylation of Tau proteins and also by sphingolipids disturbances. These changes lead to oxidative stress, mitochondria dysfunction, synaptic loss and neuro-inflammation. It is known that A may promote ceramides formation and reversely, ceramides could stimulate A peptides release. However, the effect of ceramide and sphingosine-1-phosphate (S1P) on APP metabolism has not been fully elucidated. In this study we investigated the role of ceramide and S1P on APP metabolism. Moreover, the effect of ceramide and SEW 2871 (agonist for S1P receptor-1) on Sirt1 (NAD+-dependent nuclear enzyme responsible for stress response) gene expression under A toxicity was analyzed. Experiments were carried out using pheochromocytoma cells (PC-12) transfected with: an empty vector (used as a control), human wild-type APP gene (APPwt) and Swedish mutated (K670M/N671L) APP gene (APPsw). Our results indicated that C2-ceramide significantly decreased the viability of the APPwt, APPsw as well as empty vector-transfected PC12 cells. It was observed that C2-ceramide had no significant effect on the mRNA level of - and -secretase in APPwt and APPsw cells. However, it significantly decreased transcription of -secretase in control cells. Results also showed a significant increase in Psen1 (crucial subunit of -secretase) gene expression in APPsw cells after incubation with C2-ceramide. We observed that SEW 2871 significantly upregulated the mRNA level of -secretase in control-empty vector-transfected cells subjected to C2-ceramide toxicity. The same tendency, though insignificant, was observed in APPwt and APPsw cells. Moreover, SEW 2871 enhanced the mRNA level of -secretase and Psen1 in APPsw cells after C2-ceramide treatment. Additionally, SEW 2871 significantly upregulated a gene expression of Sirt1 in APPwt and also APPsw cells subjected to C2-ceramide toxicity. Furthermore, it was observed that SEW 2871 significantly enhanced the viability of all investigated cells' lines probably through its positive influence on Sirt1.

中文翻译:

在阿尔茨海默氏病实验模型中,神经酰胺和SEW 2871在涉及淀粉样蛋白b前体蛋白代谢的酶转录中的作用。

阿尔茨海默氏病(AD)的特征是淀粉样前体蛋白(APP)代谢改变,淀粉样肽(A)积累,Tau蛋白过度磷酸化以及鞘脂紊乱。这些变化导致氧化应激,线粒体功能障碍,突触丧失和神经炎症。已知A 3可以促进神经酰胺的形成,反之,神经酰胺可以刺激A 1肽的释放。但是,神经酰胺和鞘氨醇-1-磷酸(S1P)对APP代谢的影响尚未完全阐明。在这项研究中,我们调查了神经酰胺和S1P在APP代谢中的作用。此外,分析了神经酰胺和SEW 2871(S1P受体1激动剂)对A1毒性下Sirt1(负责压力反应的NAD +依赖性核酶)基因表达的影响。使用转染了嗜铬细胞瘤细胞(PC-12),空载体(用作对照),人野生型APP基因(APPwt)和瑞典突变(K670M / N671L)APP基因(APPsw)进行实验。我们的结果表明,C2-神经酰胺会显着降低APPwt,APPsw以及空载体转染的PC12细胞的活力。观察到C2-神经酰胺对APPwt和APPsw细胞中α-和β-分泌酶的mRNA水平没有显着影响。然而,它显着降低了对照细胞中β-分泌酶的转录。结果还显示,与C2-神经酰胺孵育后,APPsw细胞中Psen1(β-分泌酶的关键亚基)基因表达显着增加。我们观察到SEW 2871在受C2神经酰胺毒性控制的空白载体转染的细胞中显着上调γ-分泌酶的mRNA水平。在APPwt和APPsw细胞中观察到相同的趋势,尽管微不足道。此外,SEW 2871增强了C2-神经酰胺处理后APPsw细胞中γ-分泌酶和Psen1的mRNA水平。另外,SEW 2871显着上调了APPwt以及遭受C2-神经酰胺毒性的APPsw细胞中Sirt1的基因表达。此外,观察到SEW 2871可能通过对Sirt1的积极影响而显着增强了所有被研究细胞系的生存能力。另外,SEW 2871显着上调了APPwt以及遭受C2-神经酰胺毒性的APPsw细胞中Sirt1的基因表达。此外,观察到SEW 2871可能通过对Sirt1的积极影响而显着增强了所有被研究细胞系的生存能力。另外,SEW 2871显着上调了APPwt以及遭受C2-神经酰胺毒性的APPsw细胞中Sirt1的基因表达。此外,观察到SEW 2871可能通过对Sirt1的积极影响而显着增强了所有被研究细胞系的生存能力。
更新日期:2019-11-01
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