Graduate School of Pharmaceutical Sciences , Kyoto University , 46-29 Yoshida-Shimoadachi-cho , Sakyo-ku , Kyoto 606-8501 , Japan.
Graduate School of Medicine and Pharmaceutical Sciences , University of Toyama , 2630 Sugitani , Toyama 930-0194 , Japan.
ACS Chem Neurosci. 2019 Jan 16;10(1):563-572. doi: 10.1021/acschemneuro.8b00424. Epub 2018 Oct 11.
The abnormal aggregation of amyloid β-protein (Aβ) is considered central in the pathogenesis of Alzheimer's disease. We focused on membrane-mediated amyloidogenesis and found that amyloid fibrils formed on monosialoganglioside GM1 clusters were more toxic than those formed in aqueous solution. In this study, we investigated the structure of the toxic fibrils by Aβ-(1-40) in detail in comparison with less-toxic fibrils formed in aqueous solution. The less-toxic fibrils contain in-resister parallel β-sheets, whereas the structure of the toxic fibrils is unknown. Atomic force microscopy revealed that the toxic fibrils had a flat, tape-like morphology composed of a single β-sheet layer. Isotope-edited infrared spectroscopy indicated that almost the entire sequence of Aβ is included in the β-sheet. Chemical cross-linking experiments using Cys-substituted Aβs suggested that the fibrils mainly contained both in-resister parallel and two-residue-shifted antiparallel β-sheet structures. Solid-state NMR experiments also supported this conclusion. Thus, the toxic fibrils were found to possess a novel unique structure.
淀粉样 β-蛋白 (Aβ) 的异常聚集被认为是阿尔茨海默病发病机制的核心。我们专注于膜介导的淀粉样蛋白形成，并发现 Aβ 在单唾液酸神经节苷脂 GM1 簇上形成的纤维比在水溶液中形成的纤维毒性更大。在这项研究中，我们通过 Aβ-(1-40) 详细研究了毒性纤维的结构，与在水溶液中形成的毒性较小的纤维进行了比较。毒性较小的纤维含有抵抗平行β-折叠，而毒性纤维的结构尚不清楚。原子力显微镜显示，毒性纤维具有由单个β-折叠层组成的平坦、带状形态。同位素编辑红外光谱表明，Aβ 的几乎整个序列都包含在β-折叠中。使用 Cys 取代的 Aβs 进行的化学交联实验表明，纤维主要含有抵抗平行和两个残基移位的反平行β-折叠结构。固态 NMR 实验也支持了这一结论。因此，发现毒性纤维具有独特的新颖结构。
