Different mechanisms of oxidative stress and neurotoxicity for Alzheimer's Aβ(1-42) and Aβ(25-35)
Different mechanisms of oxidative stress and neurotoxicity for Alzheimer's Aβ(1-42) and Aβ(25-35)
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DOI：
10.1021/ja010452r
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发表时间：
2001-06-20
影响因子：
15
通讯作者：
Butterfield, DA
中科院分区：
文献类型：
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作者：
Varadarajan, S;Kanski, J;Butterfield, DA
淀粉样β肽（A β）诱导的氧化应激与阿尔茨海默病（AD）脑中观察到的神经变性有关。然而，在AD脑中发现的A β的主要形式A β（1-42）引起氧化应激和神经毒性的机制仍然未知。许多实验室已经使用全长肽的较小的11个氨基酸片段A β（25-35）作为AD研究中的方便替代物，因为较小的肽模拟天然全长肽的几种毒理学和氧化应激特性。我们观察到截短的肽比母体A β（1-42）毒性更快并引起更多的氧化损伤，这使我们研究了A β（25-35）毒性增强的原因，以深入了解这些肽的作用机制。这些研究表明，两种不同的机制可能在两种肽中起作用;然而，肽中的单个甲硫氨酸残基似乎在这两种机制中起着至关重要的作用。蛋氨酸在qs（25-35）的C-末端似乎是其夸大效应的原因。当A β（1-42）序列中的下一个氨基酸（缬氨酸）附加到A β（25-35）上时，所得肽A β（25-36）（其中甲硫氨酸不再是C-末端）对培养的神经元既没有毒性，也不会引起氧化损伤。此外，将甲硫氨酸的硫氧化为亚砜消除了A β（25-35）和A β（1-42）的破坏作用。甲硫氨酸在所观察到的A β肽的性质中的假定的机械作用在所获得的结果的上下文中进行了讨论，这是A β（1-42）诱导的氧化应激在AD脑中发现的神经变性中的作用。
Oxidative stress induced by amyloid beta -peptide (A beta) has been implicated in the neurodegeneration observed in Alzheimer's disease (AD) brain. However, the mechanism by which the predominant form of A beta found in AD brains, A beta (1-42), causes oxidative stress and neurotoxicity remains unknown. Numerous laboratories have used the smaller 11-amino acid fragment of the full-length peptide, A beta (25-35), as a convenient alternative in AD investigations since the smaller peptide mimics several of the toxicological and oxidative stress properties of the native full-length peptide. Our observation that the truncated peptide is more rapidly toxic and causes more oxidative damage than the parent A beta (1-42) led us to investigate the cause for this enhanced toxicity of A beta (25-35) in order to gain insight into the mechanism of action of these peptides. These studies reveal that two different mechanisms may be operative in the two peptides; however, the single methionine residue in the peptides appears to play a crucial role in both mechanisms. That methionine is C-terminal in qs(25-35) seems to be the cause for its exaggerated effects. When the next amino acid in the sequence of A beta (1-42) (valine) is appended to A beta (25-35), the resultant peptide, A beta (25-36), in which methionine is no longer C-terminal, is neither toxic to cultured neurons nor does it cause oxidative damage. Additionally, oxidizing the sulfur of methionine to a sulfoxide abrogates the damaging effects of both A beta (25-35) and A beta (1-42). The putative mechanistic role of methionine in the observed properties of A beta peptides is discussed in the context of the obtained results as is the role of A beta (1-42)-induced oxidative stress in the neurodegeneration found in AD brain.