Gao Guanbin, Zhang Ting, Zhang Wenkang, Luo Zhuoying, Zhang Zijun, Gu Zhenhua, Yu Liangchong, Mu Qinxue, Sun Taolei
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China.
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China.
J Colloid Interface Sci. 2022 Sep;621:67-76. doi: 10.1016/j.jcis.2022.04.085. Epub 2022 Apr 16.
Revealing the disaggregating mechanism of amyloids fibrils under nanomaterials action is a key issue for their successful future use in therapy of neurodegenerative and overall amyloid-related diseases. Herein a gold nanocluster stabilized by Arg-Cys dipeptide (Au(RC)NCs) was synthesized to investigate its disaggregation activity toward Aβ fibrils by using Thioflavin-T (ThT) fluorescence assay and atomic force microscopy. It was demonstrated that Au(RC)NCs is very effective in disaggregating preformed Aβ fibrils, and characterized by the ultra-low apparent completely disaggregation concentration at the dose of 10 μg·mL. A possible disaggregation mechanism based on Au(RC)NCs triggering the disassembly of Aβ fibrils into a dynamic equilibrium was proposed. The introduction of Au(RC)NCs with appropriate dose (5 μg·mL) can trigger the disassemble process of mature Aβ fibrils into a critical state, at this very moment, if there is no more nano-disassembler, destruction of old Aβ fibrils and formation of new Aβ fibrils are thus in permanent dynamic equilibrium; in contrast, if there is more nano-disassembler (>10 μg·mL), the dynamic equilibrium prefer to shift to the direction of Aβ further disassembly. Moreover, Au(RC)NCs with dosage over 10 μg·mL exhibited superb protection effect against Aβ-induced cytotoxicity in cell experiments. This study not only proposed a possible disassembly mechanism of amyloids fibrils under nanomaterials action, but also provide Au(RC)NCs as a promising high-effective nano-disassembler to disassemble unwanted amyloid aggregates.
揭示纳米材料作用下淀粉样纤维的解聚机制是其未来成功用于治疗神经退行性疾病及其他淀粉样相关疾病的关键问题。在此，合成了一种由精氨酸 - 半胱氨酸二肽稳定的金纳米簇（Au(RC)NCs），通过硫黄素 - T（ThT）荧光测定法和原子力显微镜研究其对Aβ纤维的解聚活性。结果表明，Au(RC)NCs在解聚预先形成的Aβ纤维方面非常有效，其特征在于在剂量为10μg·mL时具有超低的表观完全解聚浓度。提出了一种基于Au(RC)NCs触发Aβ纤维解聚为动态平衡的可能解聚机制。引入适当剂量（5μg·mL）的Au(RC)NCs可触发成熟Aβ纤维的解聚过程进入临界状态，此时，如果没有更多的纳米解聚剂，旧的Aβ纤维的破坏和新的Aβ纤维的形成将处于永久的动态平衡；相反，如果有更多的纳米解聚剂（>10μg·mL），动态平衡更倾向于向Aβ进一步解聚的方向移动。此外，在细胞实验中，剂量超过10μg·mL的Au(RC)NCs对Aβ诱导的细胞毒性表现出极好的保护作用。本研究不仅提出了纳米材料作用下淀粉样纤维可能的解聚机制，还提供了Au(RC)NCs作为一种有前景的高效纳米解聚剂来拆解不需要的淀粉样聚集体。
