Structural Insight into an Alzheimer's Brain-Derived Spherical Assembly of Amyloid β by Solid-State NMR.
Structural Insight into an Alzheimer's Brain-Derived Spherical Assembly of Amyloid β by Solid-State NMR.
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DOI：
10.1021/jacs.5b03373
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发表时间：
2015-05-27
影响因子：
15
通讯作者：
Ishii Y
中科院分区：
文献类型：
--
作者：
Parthasarathy S;Inoue M;Xiao Y;Matsumura Y;Nabeshima Y;Hoshi M;Ishii Y
越来越多的证据表明，包括阿尔茨海默氏病（AD）在内的各种神经退行性疾病与淀粉样蛋白的细胞毒性扩散聚集体有关，淀粉样蛋白是蛋白质错误折叠中的亚稳态中间物种。这项研究首次对一种称为淀粉样蛋白球体 (ASPD) 的中间体进行了位点特异性结构研究，这是一种由低聚淀粉样蛋白 -β (Aβ) 组成的 AD 衍生神经毒素。使用 ASPD 特异性“构象”抗体进行电子显微镜和免疫学分析，确定 42 个残基 Aβ(1-42) 的合成 ASPD 是从 AD 患者中提取的天然 ASPD 的优异结构/形态类似物，其水平与 AD 的严重程度相关。对大约 20 个残基和链间距离的 13C 固态 NMR 分析表明，合成的 ASPD 由含有平行 β 折叠的均质单一构象异构体组成。这些结果提供了对天然 ASPD 的深刻见解，表明 Aβ 很可能在 AD 大脑中自组装成具有 β-折叠结构的有毒中间体。该方法可应用于与淀粉样蛋白疾病相关的各种中间体。
Accumulating evidence suggests that various neurodegenerative diseases, including Alzheimer’s disease (AD), are linked to cytotoxic diffusible aggregates of amyloid proteins, which are metastable intermediate species in protein misfolding. This study presents the first site-specific structural study on an intermediate called amylospheroid (ASPD), an AD-derived neurotoxin composed of oligomeric amyloid-β (Aβ). Electron microscopy and immunological analyses using ASPD-specific “conformational” antibodies established synthetic ASPD for the 42-residue Aβ(1–42) as an excellent structural/morphological analogue of native ASPD extracted from AD patients, the level of which correlates with the severity of AD. 13C solid-state NMR analyses of approximately 20 residues and interstrand distances demonstrated that the synthetic ASPD is made of a homogeneous single conformer containing parallel β-sheets. These results provide profound insight into the native ASPD, indicating that Aβ is likely to self-assemble into the toxic intermediate with β-sheet structures in AD brains. This approach can be applied to various intermediates relevant to amyloid diseases.
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影响因子：
3.2
作者：
Bertini, Ivano;Gallo, Gianluca;Ravera, Enrico
通讯作者：
Ravera, Enrico
影响因子：
5.6
作者：
Tay WM;Huang D;Rosenberry TL;Paravastu AK
通讯作者：
Paravastu AK
DOI：
10.1073/pnas.1203193109
发表时间：
2012-05-15
影响因子：
11.1
作者：
Stroud, James C.;Liu, Cong;Eisenberg, David
通讯作者：
Eisenberg, David
影响因子：
15
作者：
Chimon, S;Ishii, Y
通讯作者：
Ishii, Y
影响因子：
11.4
作者：
Karpinar, Damla Pinar;Balija, Madhu Babu Gajula;Zweckstetter, Markus
通讯作者：
Zweckstetter, Markus