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粉样β自组合的连续阶段以固态核磁共振与动态核极化为特征

Alexey Potapov¹, Wai-Ming Yau¹, Rodolfo Ghirlando¹

¹†Laboratory of Chemical Physics and ‡Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, United States.

Journal of the American Chemical Society

|June 13, 2015

概括

阿尔茨海默病涉及粉样蛋白-β (Aβ) 自组合. 动态核极化固态NMR揭示了Aβ40单体获得了结构秩序,但直到最后阶段缺乏纤维结构,为有毒物种提供了新的见解.

科学领域:

生物化学生物化学
神经科学是一个神经科学.
结构生物学结构生物学

背景情况:

阿尔茨海默病 (AD) 与大脑中的粉样β (Aβ) 自我组合有关.
粉样纤维是最终产品,但有毒的寡合体和原纤维细胞中间体的理解较少.
描述这些过渡物种对于理解AD病变的产生至关重要.

研究的目的:

在自我组装过程中监测粉样蛋白-β 40 (Aβ40) 的结构演变.
使用先进的NMR技术来表征短暂的寡合和原纤维细胞中间体.
为了研究Aβ中间体和成熟纤维之间的结构差异.

主要方法:

固态核磁共振 (ssNMR) 用于研究Aβ40.0.
动态核极化 (DNP) 增强的ssNMR使得在低温 (<30K) 下对冷溶液进行测量.
分析了ssNMR化学转移和自旋极化转移,以确定分子构造和超分子结构.

主要成果:

观察到从单体/小寡体到较大的寡体,原纤维和纤维的结构顺序的单调增加.
主要的分子构造在所有组装阶段都保持了质量相似.
纤维素特征的注册平行β片超分子结构,直到最后的纤维素阶段才形成.

结论:

用DNP增强的ssNMR是研究/蛋白自组装中间体的强大工具.
在组装初期,Aβ40采用类似的分子构造,但纤维状超分子结构的发展较晚.
了解Aβ中间体的结构转变可能会揭示阿尔茨海默病治疗的点.

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