Vitamin E: Curse or benefit in Alzheimer's disease? A systematic investigation of the impact of α-, γ- and δ-tocopherol on Aβ generation and degradation in neuroblastoma cells
Vitamin E: Curse or benefit in Alzheimer's disease? A systematic investigation of the impact of α-, γ- and δ-tocopherol on Aβ generation and degradation in neuroblastoma cells
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DOI：
10.1007/s12603-015-0506-z
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发表时间：
2015-06-01
影响因子：
5.8
通讯作者：
Hartmann, T.
中科院分区：
文献类型：
--
作者：
Grimm, M. O. W.;Stahlmann, C. P.;Hartmann, T.
维生素E是一类包括生育酚在内的亲脂化合物，具有很高的抗氧化性能。由于阿尔茨海默病(AD)中脂质过氧化水平的升高和活性氧化物种的增加，许多人试图利用维生素E的抗氧化作用来减缓AD的进展。除了这些研究的混合结果外，关于维生素E对导致淀粉样β蛋白产生和降解的机制的影响尚不清楚，淀粉样β蛋白的产生和降解是AD的典型病理特征之一。在这里，我们系统地研究了不同生育酚对神经细胞系中Aβ产生和降解的影响。除了淀粉样β水平外，还探讨了导致Aβ产生和降解的机制。令人惊讶的是，所有生育酚都显示出通过促进Aβ产生和减少Aβ降解来增加Aβ水平。β-分泌酶和伽马-分泌酶的活性增加，从而促进了β-分泌酶的产生。这些分泌酶不会受到直接影响，但生育酚会增加它们的蛋白质水平和表达。我们可以确定单一生育酚之间的显著差异；尽管α-生育酚对Aβ产生的影响很小，但β-生育酚显示出最高的增加Aβ产生的效力。除了Aβ的产生，Aβ的清除也因影响主要的Aβ降解酶之一的IDE而减少。我们的结果表明，除了维生素E的有益抗氧化作用外，生育酚对于AD也有提高淀粉样β水平的效力，这一点在所分析的生育酚中有所不同。因此，我们建议需要进一步的研究，以澄清这些不同的维生素E物种在AD方面的潜在作用，并确定包含抗氧化特性但不具有淀粉样变性潜力的形式。
The E vitamins are a class of lipophilic compounds including tocopherols, which have high antioxidative properties. Because of the elevated lipid peroxidation and increased reactive oxidative species in Alzheimer's disease (AD) many attempts have been made to slow down the progression of AD by utilizing the antioxidative action of vitamin E. Beside the mixed results of these studies nothing is known about the impact of vitamin E on the mechanisms leading to amyloid-beta production and degradation being responsible for the plaque formation, one of the characteristic pathological hallmarks in AD. Here we systematically investigate the influence of different tocopherols on A beta production and degradation in neuronal cell lines.Beside amyloid-beta level the mechanisms leading to A beta production and degradation are examined.Surprisingly, all tocopherols have shown to increase A beta level by enhancing the A beta production and decreasing the A beta degradation. A beta production is enhanced by an elevated activity of the involved enzymes, the beta- and gamma-secretase. These secretases are not directly affected, but tocopherols increase their protein level and expression. We could identify significant differences between the single tocopherols; whereas alpha-tocopherol had only minor effects on A beta production, delta-tocopherol showed the highest potency to increase A beta generation. Beside A beta production, A beta clearance was decreased by affecting IDE, one of the major A beta degrading enzymes.Our results suggest that beside the beneficial antioxidative effects of vitamin E, tocopherol has in respect to AD also a potency to increase the amyloid-beta level, which differ for the analysed tocopherols. We therefore recommend that further studies are needed to clarify the potential role of these various vitamin E species in respect to AD and to identify the form which comprises an antioxidative property without having an amyloidogenic potential.