Zhang Wenkang, Gao Guanbin, Ma Zhongjie, Luo Zhuoying, He Meng, Sun Taolei
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China.
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China.
Natl Sci Rev. 2020 Apr;7(4):763-774. doi: 10.1093/nsr/nwz215. Epub 2019 Dec 20.
The misfolding of amyloid-β (Aβ) peptides from the natural unfolded state to β-sheet structure is a critical step, leading to abnormal fibrillation and formation of endogenous Aβ plaques in Alzheimer's disease (AD). Previous studies have reported inhibition of Aβ fibrillation or disassembly of exogenous Aβ fibrils . However, soluble Aβ oligomers have been reported with increased cytotoxicity; this might partly explain why current clinical trials targeting disassembly of Aβ fibrils by anti-Aβ antibodies have failed so far. Here we show that Au(CR) (a new Au nanocluster modified by Cys-Arg (CR) dipeptide) is able to completely dissolve exogenous mature Aβ fibrils into monomers and restore the natural unfolded state of Aβ peptides from misfolded β-sheets. Furthermore, the cytotoxicity of Aβ fibrils when dissolved by Au(CR) is fully abolished. More importantly, Au(CR) is able to completely dissolve endogenous Aβ plaques in brain slices from transgenic AD model mice. In addition, Au(CR) has good biocompatibility and infiltration ability across the blood-brain barrier. Taken together, this work presents a promising therapeutics candidate for AD treatment, and manifests the potential of nanotechnological approaches in the development of nanomedicines.
淀粉样β蛋白（Aβ）肽从天然未折叠状态错误折叠为β-折叠结构是关键步骤，会导致异常纤维化并在阿尔茨海默病（AD）中形成内源性Aβ斑块。先前的研究报道了对Aβ纤维化的抑制或外源性Aβ纤维的拆解。然而，有报道称可溶性Aβ寡聚体具有更高的细胞毒性；这可能部分解释了目前针对通过抗Aβ抗体拆解Aβ纤维的临床试验为何迄今失败。在此我们表明，Au(CR)（一种由半胱氨酸-精氨酸（CR）二肽修饰的新型金纳米团簇）能够将外源性成熟Aβ纤维完全溶解为单体，并将Aβ肽从错误折叠的β-折叠恢复到天然未折叠状态。此外，Au(CR)溶解Aβ纤维时的细胞毒性被完全消除。更重要的是，Au(CR)能够完全溶解转基因AD模型小鼠脑切片中的内源性Aβ斑块。此外，Au(CR)具有良好的生物相容性和穿越血脑屏障的渗透能力。综上所述，这项工作为AD治疗提供了一个有前景的治疗候选物，并体现了纳米技术方法在纳米药物开发中的潜力。
