Friedemann Merlin, Helk Eneken, Tiiman Ann, Zovo Kairit, Palumaa Peep, Tõugu Vello
Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia.
Biochem Biophys Rep. 2015 Jul 30;3:94-99. doi: 10.1016/j.bbrep.2015.07.017. eCollection 2015 Sep.
Aggregation of Aβ peptides into amyloid plaques is considered to trigger the Alzheimer's disease (AD), however the mechanism behind the AD onset has remained elusive. It is assumed that the insoluble Aβ aggregates enhance oxidative stress (OS) by generating free radicals with the assistance of bound copper ions. The aim of our study was to establish the role of Met35 residue in the oxidation and peptide aggregation processes. Met35 can be readily oxidized by HO. The fibrillization of Aβ with Met35 oxidized to sulfoxide was three times slower compared to that of the regular peptide. The fibrils of regular and oxidized peptides looked similar under transmission electron microscopy. The relatively small inhibitory effect of methionine oxidation on the fibrillization suggests that the possible variation in the Met oxidation state should not affect the in vivo plaque formation. The peptide oxidation pattern was more complex when copper ions were present: addition of one oxygen atom was still the fastest process, however, it was accompanied by multiple unspecific modifications of peptide residues. Addition of copper ions to the Aβ with oxidized Met35 in the presence of HO, resulted a similar pattern of nonspecific modifications, suggesting that the one-electron oxidation processes in the peptide molecule do not depend on the oxidation state of Met35 residue. Thus, it can be concluded that Met35 residue is not a part of the radical generating mechanism of Aβ-Cu(II) complex.
Aβ肽聚集成淀粉样斑块被认为是引发阿尔茨海默病（AD）的原因，然而AD发病背后的机制仍然难以捉摸。据推测，不溶性Aβ聚集体在结合的铜离子协助下通过产生自由基来增强氧化应激（OS）。我们研究的目的是确定Met35残基在氧化和肽聚集过程中的作用。Met35很容易被羟基自由基（HO）氧化。与正常肽相比，Met35氧化为亚砜的Aβ纤维化速度慢三倍。在透射电子显微镜下，正常肽和氧化肽的纤维看起来相似。甲硫氨酸氧化对纤维化的抑制作用相对较小，这表明Met氧化态的可能变化不应影响体内斑块的形成。当存在铜离子时，肽的氧化模式更为复杂：添加一个氧原子仍然是最快发生的过程，然而，它伴随着肽残基的多种非特异性修饰。在HO存在的情况下，向氧化的Met35的Aβ中添加铜离子，产生了类似的非特异性修饰模式，这表明肽分子中的单电子氧化过程不依赖于Met35残基的氧化态。因此，可以得出结论，Met35残基不是Aβ-Cu（II）复合物自由基产生机制的一部分。
