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Structural variation in amyloid-beta fibrils from Alzheimer's disease clinical subtypes

机译：阿尔茨海默氏病临床亚型的β-淀粉样蛋白原纤维的结构变异

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摘要

Aggregation of amyloid-beta peptides into fibrils or other self-assembled states is central to the pathogenesis of Alzheimer's disease. Fibrils formed in vitro by 40- and 42-residue amyloid-beta peptides (A beta 40 and A beta 42) are polymorphic, with variations in molecular structure that depend on fibril growth conditions(1-12). Recent experiments(1,13-16) suggest that variations in amyloid-beta fibril structure in vivo may correlate with variations in Alzheimer's disease phenotype, in analogy to distinct prion strains that are associated with different clinical and pathological phenotypes(17-19). Here we investigate correlations between structural variation and Alzheimer's disease phenotype using solid-state nuclear magnetic resonance (ssNMR) measurements on A beta 40 and A beta 42 fibrils prepared by seeded growth from extracts of Alzheimer's disease brain cortex. We compared two atypical Alzheimer's disease clinical subtypes-the rapidly progressive form (r-AD) and the posterior cortical atrophy variant (PCA-AD)-with a typical prolonged-duration form (t-AD). On the basis of ssNMR data from 37 cortical tissue samples from 18 individuals, we find that a single A beta 40 fibril structure is most abundant in samples from patients with t-AD and PCA-AD, whereas A beta 40 fibrils from r-AD samples exhibit a significantly greater proportion of additional structures. Data for A beta 42 fibrils indicate structural heterogeneity in most samples from all patient categories, with at least two prevalent structures. These results demonstrate the existence of a specific predominant A beta 40 fibril structure in t-AD and PCA-AD, suggest that r-AD may relate to additional fibril structures and indicate that there is a qualitative difference between A beta 40 and A beta 42 aggregates in the brain tissue of patients with Alzheimer's disease.
机译：淀粉样β肽聚集成纤维或其他自组装状态是阿尔茨海默氏病发病机理的关键。 40和42个残基的淀粉样β肽（A beta 40和A beta 42）在体外形成的原纤维是多态的，分子结构的变化取决于原纤维的生长条件（1-12）。最近的实验（1,13-16）表明，体内淀粉样β原纤维结构的变化可能与阿尔茨海默氏病表型的变化相关，这类似于与不同临床和病理学表型相关的distinct病毒株（17-19）。在这里，我们使用固态核磁共振（ssNMR）测量方法对结构变化与阿尔茨海默氏病表型之间的相关性进行了研究，该方法是通过从阿尔茨海默氏病大脑皮层的种子生长中制备的A beta 40和A beta 42原纤维进行的。我们比较了两种非典型的阿尔茨海默氏病的临床亚型，即快速进展型（r-AD）和后皮质萎缩变体（PCA-AD）与典型的持续时间延长型（t-AD）。根据来自18个个体的37个皮质组织样本的ssNMR数据，我们发现，来自t-AD和PCA-AD患者的样本中单个A beta 40原纤维结构最为丰富，而来自r-AD的A beta 40原纤维样品显示出更大比例的附加结构。 A beta 42原纤维的数据表明，在来自所有患者类别的大多数样品中，结构异质性至少具有两个普遍的结构。这些结果表明在t-AD和PCA-AD中存在特定的主要A beta 40原纤维结构，表明r-AD可能与其他原纤维结构有关，并且表明A beta 40和A beta 42之间存在质的差异。聚集在阿尔茨海默氏病患者的脑组织中。

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  • 来源
    《Nature》 |2017年第7636期|217-221|共5页
  • 作者

    Qiang Wei; Yau Wai-Ming; Lu Jun-Xia; Collinge John; Tycko Robert;

  • 作者单位

    NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA|SUNY Binghamton, Dept Chem, Binghamton, NY 13902 USA;

    NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA;

    NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA|ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;

    UCL Inst Neurol, MRC Prion Unit, London WC1N 3BG, England|UCL Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England;

    NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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