Aβ-40 Y10F increases βfibrils formation but attenuates the neurotoxicity of amyloid-β peptide.
Aβ-40 Y10F increases βfibrils formation but attenuates the neurotoxicity of amyloid-β peptide.
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DOI：
10.3390/ijms13055324
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发表时间：
2012
影响因子：
5.6
通讯作者：
Jiang Z
中科院分区：
文献类型：
--
作者：
Dai X;Chang P;Liu W;Xu K;Sun Y;Zhu S;Jiang Z
阿尔茨海默病（Alzheimer's disease，AD）是一种以β淀粉样蛋白（amyloid-β peptide，Aβ）异常聚集于细胞外的老年斑为特征的疾病。由于酪氨酰自由基的形成，酪氨酸残基（Tyr-10）被认为在Aβ诱导的神经毒性中很重要。为了降低交联的可能性，我们设计了一种Aβ-40类似物（Aβ-40 Y10 F），其中酪氨酸残基被结构相似的残基苯丙氨酸取代。通过硫磺素T（ThT）试验测定聚集率，其中Aβ-40 Y10 F比野生型Aβ更快更强地形成折叠构象系综。随后的生物物理测试证实了ThT测定的结果，表明所测量的β-聚集的增加可能主要是由于取代后疏水性的增强以及因此内在β-折叠形成的倾向。然而，与Aβ-40相比，Aβ-40 Y10 F的神经毒性显著降低，这可能部分归因于过氧化氢的生成减少。这些发现可能有助于进一步了解Aβ结构的扰动对其纤维化的影响。
Alzheimer’s disease (AD) is characterized by the abnormal aggregation of amyloid-β peptide (Aβ) in extracellular deposits known as senile plaques. The tyrosine residue (Tyr-10) is believed to be important in Aβ-induced neurotoxicity due to the formation of tyrosyl radicals. To reduce the likelihood of cross-linking, here we designed an Aβ-40 analogue (Aβ-40 Y10F) in which the tyrosine residue was substituted by a structurally similar residue, phenylalanine. The aggregation rate was determined by the Thioflavin T (ThT) assay, in which Aβ-40 Y10F populated an ensemble of folded conformations much quicker and stronger than the wild type Aβ. Biophysical tests subsequently confirmed the results of the ThT assay, suggesting the measured increase of β-aggregation may arise predominantly from enhancement of hydrophobicity upon substitution and thus the propensity of intrinsic β-sheet formation. Nevertheless, Aβ-40 Y10F exhibited remarkably decreased neurotoxicity compared to Aβ-40 which could be partly due to the reduced generation of hydrogen peroxide. These findings may lead to further understanding of the structural perturbation of Aβ to its fibrillation.
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