The Alzheimer's amyloid-β(1-42) peptide forms off-pathway oligomers and fibrils that are distinguished structurally by intermolecular organization.
The Alzheimer's amyloid-β(1-42) peptide forms off-pathway oligomers and fibrils that are distinguished structurally by intermolecular organization.
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DOI：
10.1016/j.jmb.2013.04.003
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发表时间：
2013-07-24
影响因子：
5.6
通讯作者：
Paravastu AK
中科院分区：
文献类型：
--
作者：
Tay WM;Huang D;Rosenberry TL;Paravastu AK
越来越多的证据表明，淀粉样蛋白-β(Aβ)的可溶性聚集体会引发神经毒性，最终导致阿尔茨海默病患者的痴呆。对可溶性聚集体结构的了解将加深我们对结构和毒性之间关系的理解。本课题组报道了一种稳定且均一的Aβ(1-42)低聚物的制备，并用各种生物物理技术对其进行了表征。在这里，我们进一步分析了这一物种的固体核磁共振(核磁共振)谱，并将核磁共振结果与对淀粉样纤维的类似观察结果进行了比较。对Aβ(1-42)低聚物的核磁共振实验揭示了标记残基的化学位移，表明了β链的二级结构。二维DARR实验结果表明，I31脂肪族和F19芳香族碳接近。同位素稀释实验进一步表明，F19和I31之间的这些接触是分子间的，与其他人提出的Aβ寡聚体模型相反。对于Aβ(1-42)纤维，我们观察到相似的核磁共振线形和侧链间接触，表明相似的二级和四元结构。通过PITHIRDS-CT实验中观察到的分子间~(13)C-~(13)C偶极耦合的测量，观察到A-β(1-42)低聚物与原纤维之间最显著的结构差异。PITHIRDS-CT数据表明，与纤维不同，低聚物不具有登记内平行β-Sheet的特征。Aβ(1-42)寡聚体和纤维的结构异同表明，折叠的β链多肽构象是在自组装过程的早期形成的，而寡聚体和纤维的主要不同在于分子间的组织方案。Aβ(1-42)低聚物和纤维之间独特的分子间排列可以解释为什么这种低聚状态似乎偏离了单体自组装成纤维的途径。
Increasing evidence suggests that soluble aggregates of amyloid-β (Aβ) initiate the neurotoxicity that eventually leads to dementia in Alzheimer’s disease. Knowledge of soluble aggregate structures will enhance our understanding of the relationship between structures and toxicities. Our group has reported a stable and homogeneous preparation of Aβ(1–42) oligomers that has been characterized by various biophysical techniques. Here, we have further analyzed this species by solid state nuclear magnetic resonance (NMR) spectroscopy and compared NMR results to similar observations on amyloid fibrils. NMR experiments on Aβ(1–42) oligomers reveal chemical shifts of labeled residues that are indicative of β-strand secondary structure. Results from 2D DARR experiments indicate proximities between I31 aliphatic and F19 aromatic carbons. An isotope dilution experiment further indicates that these contacts between F19 and I31 are intermolecular, contrary to models of Aβ oligomers proposed previously by others. For Aβ(1–42) fibrils we observed similar NMR lineshapes and inter-sidechain contacts, indicating similar secondary and quaternary structures. The most prominent structural differences between Aβ(1–42) oligomers and fibrils were observed through measurements of inter-molecular 13C-13C dipolar couplings observed in PITHIRDS-CT experiments. PITHIRDS-CT data indicate that, unlike fibrils, oligomers are not characterized by in-register parallel β-sheets. Structural similarities and differences between Aβ(1–42) oligomers and fibrils suggest that folded β-strand peptide conformations form early in the course of self-assembly, and that oligomers and fibrils differ primarily in schemes of inter-molecular organization. Distinct inter-molecular arrangements between Aβ(1–42) oligomers and fibrils may explain why this oligomeric state appears off-pathway for monomer self-assembly to fibrils.
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影响因子：
4.4
作者：
BENNETT, AE;RIENSTRA, CM;GRIFFIN, RG
通讯作者：
GRIFFIN, RG
DOI：
10.1021/j150451a002
发表时间：
1947-01-01
期刊：
JOURNAL OF PHYSICAL AND COLLOID CHEMISTRY
影响因子：
--
作者：
DEBYE, P
通讯作者：
DEBYE, P
影响因子：
30.8
作者：
HENDRIKS, L;VANDUIJN, CM;VAN BROECKHOVEN, C
通讯作者：
VAN BROECKHOVEN, C
影响因子：
4.4
作者：
Ishii, Y
通讯作者：
Ishii, Y
影响因子：
25
作者：
Cleary, JP;Walsh, DM;Ashe, KH
通讯作者：
Ashe, KH