Key Laboratory of Industrial Fermentation Microbiology , Tianjin University of Science & Technology , Ministry of Education, Tianjin , 300457 , P. R. China.
Tianjin Key Laboratory of Industrial Microbiology , Tianjin University of Science & Technology , Tianjin , 300457 , P. R. China.
ACS Chem Neurosci. 2019 Jan 16;10(1):588-598. doi: 10.1021/acschemneuro.8b00441. Epub 2018 Oct 18.
The fibrillogenesis of amyloid-β protein (Aβ) is considered a crucial factor in the pathogenesis of Alzheimer's disease (AD). Hence, inhibiting Aβ fibrillogenesis is regarded as the primary therapeutic strategy for the prevention and treatment of AD. However, the development of effective inhibitors against Aβ fibrillogenesis has faced significant challenges. Previous studies have shown that pristine single-walled carbon nanotubes (SWNTs) can inhibit fibrillogenesis of some amyloid proteins. However, the poor dispersibility of SWNTs in an aqueous environment greatly hinders their inhibitory efficacy. Here, we examined the inhibitory activity of hydroxylated SWNTs (SWNT-OH) on the aggregation and cytotoxicity of Aβ using thioflavin T (ThT) fluorescence, atomic force microscopy (AFM), cellular viability assays, and molecular dynamics (MD) simulations. ThT and AFM results showed that SWNT-OH inhibits Aβ fibrillogenesis and disaggregates preformed amyloid fibrils in a dose-dependent manner. Furthermore, the ratio of hydroxyl groups in SWNT-OH is crucial for their effect against Aβ aggregation. SWNT-OH exerted cytoprotective effects against Aβ fibrillation-induced cytotoxicity. The results of free-energy decomposition studies based on MD simulations revealed that nonpolar interactions, and especially van der Waals forces, contributed most of the free energy of binding in the SWNT-OH-Aβ complex. Two regions of the Aβ pentamer were identified to interact with SWNT-OH, spanning H13-Q15 and V36-G38. The findings presented here will contribute to a comprehensive understanding of the inhibitory effect of hydroxylated nanoparticles against Aβ fibrillogenesis, which is critical for the search for more effective agents that can counteract amyloid-mediated pathologies.
淀粉样蛋白-β 蛋白 (Aβ) 的纤维形成被认为是阿尔茨海默病 (AD) 发病机制中的关键因素。因此，抑制 Aβ 纤维形成被认为是预防和治疗 AD 的主要治疗策略。然而，开发针对 Aβ 纤维形成的有效抑制剂面临着重大挑战。先前的研究表明，原始的单壁碳纳米管 (SWNTs) 可以抑制一些淀粉样蛋白的纤维形成。然而，SWNTs 在水相中的分散性差极大地阻碍了它们的抑制效果。在这里，我们使用硫黄素 T（ThT）荧光、原子力显微镜（AFM）、细胞活力测定和分子动力学（MD）模拟研究了羟基化 SWNTs（SWNT-OH）对 Aβ 聚集和细胞毒性的抑制活性。ThT 和 AFM 结果表明，SWNT-OH 以剂量依赖的方式抑制 Aβ 纤维形成并解聚预先形成的淀粉样纤维。此外，SWNT-OH 中羟基的比例对其抑制 Aβ 聚集的效果至关重要。SWNT-OH 对 Aβ 纤维诱导的细胞毒性表现出细胞保护作用。基于 MD 模拟的自由能分解研究结果表明，非极性相互作用，特别是范德华力，对 SWNT-OH-Aβ 复合物的结合自由能贡献最大。鉴定出 Aβ 五聚体的两个区域与 SWNT-OH 相互作用，跨越 H13-Q15 和 V36-G38。本研究结果将有助于全面了解羟基化纳米粒子对 Aβ 纤维形成的抑制作用，这对于寻找更有效的对抗淀粉样蛋白介导的病理的药物具有重要意义。
