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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Seeded growth of β-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure
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Seeded growth of β-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure

机译：阿尔茨海默氏症脑源性原纤维的β-淀粉样蛋白原纤维的种子生长产生独特的原纤维结构

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摘要

Studies by solid-state nuclear magnetic resonance (NMR) of amyloid fibrils prepared in vitro from synthetic 40-residue β-amyloid (Aβ_(1-40)) peptides have shown that the molecular structure of Aβ_(1-40) fibrils is not uniquely determined by amino acid sequence. Instead, the fibril structure depends on the precise details of growth conditions. The molecular structures of β-amyloid fibrils that develop in Alzheimer's disease (AD) are therefore uncertain. We demonstrate through thioflavin T fluorescence and electron microscopy that fibrils extracted from brain tissue of deceased AD patients can be used to seed the growth of synthetic Aβ_(1-40) fibrils, allowing preparation of fibrils with isotopic labeling and in sufficient quantities for solid-state NMR and other measurements. Because amyloid structures propagate themselves in seeded growth, as shown in previous studies, the molecular structures of brain-seeded synthetic Aβ_(1-40) fibrils most likely reflect structures that are present in AD brain. Solid-state ~(13)C NMR spectra of fibril samples seeded with brain material from two AD patients were found to be nearly identical, indicating the same molecular structures. Spectra of an unseeded control sample indicate greater structural heterogeneity. ~(13)C chemical shifts and other NMR data indicate that the predominant molecular structure in brain-seeded fibrils differs from the structures of purely synthetic Aβ_(1-40) fibrils that have been characterized in detail previously. These results demonstrate a new approach to detailed structural characterization of amyloid fibrils that develop in human tissue, and to investigations of possible correlations between fibril structure and the degree of cognitive impairment and neurodegeneration in AD.
机译：固态核磁共振（NMR）对由合成的40残基β淀粉样蛋白（Aβ_（1-40））肽体外制备的淀粉样蛋白原纤维的研究表明，Aβ_（1-40）原纤维的分子结构不是由氨基酸序列唯一确定。相反，原纤维结构取决于生长条件的精确细节。因此，在阿尔茨海默氏病（AD）中发展的β-淀粉样蛋白原纤维的分子结构尚不确定。我们通过硫代黄素T荧光和电子显微镜证实，从死去的AD患者脑组织中提取的原纤维可用于播种合成Aβ_（1-40）原纤维的生长，从而可以用同位素标记制备原纤维，并为固体- NMR和其他测量。如先前的研究所示，由于淀粉样蛋白结构会在种子生长中自我繁殖，因此，大脑播种的合成Aβ_（1-40）原纤维的分子结构很可能反映了AD脑中存在的结构。发现两名AD患者的脑材料播种的原纤维样品的固态〜（13）C NMR光谱几乎相同，表明分子结构相同。未接种对照样品的光谱表明更大的结构异质性。 〜（13）C化学位移和其他NMR数据表明，脑接种原纤维中的主要分子结构与先前已详细表征的纯合成Aβ_（1-40）原纤维的结构不同。这些结果证明了一种新方法，可以详细描述人体组织中淀粉样蛋白原纤维的结构特征，并可以研究原纤维结构与AD认知障碍和神经变性程度之间的可能相关性。

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    Isam Qahwash; Richard D. Leapman; Stephen C. Meredith; Robert Tycko; Anant K. Paravastu;

  • 作者单位

    Department of Biochemistry and Molecular Biology and Department of Pathology, The University of Chicago, Chicago, IL 60637;

    Laboratory of Bioengineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892-5766;

    Department of Biochemistry and Molecular Biology and Department of Pathology, The University of Chicago, Chicago, IL 60637;

    Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520;

    Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520 Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University College of Engineering, Tallahassee, FL 32310-6046;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    alzheimer's disease; electron microscopy; solid-state nuclear magnetic resonance;

    机译：阿尔茨海默氏病;电子显微镜;固态核磁共振;

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