Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences (SLU), Box 7015, SE-750 07 Uppsala (Sweden).
Angew Chem Int Ed Engl. 2014 Nov 17;53(47):12756-60. doi: 10.1002/anie.201406357. Epub 2014 Sep 26.
Oligomeric and protofibrillar aggregates formed by the amyloid-β peptide (Aβ) are believed to be involved in the pathology of Alzheimer's disease. Central to Alzheimer pathology is also the fact that the longer Aβ42 peptide is more prone to aggregation than the more prevalent Aβ40 . Detailed structural studies of Aβ oligomers and protofibrils have been impeded by aggregate heterogeneity and instability. We previously engineered a variant of Aβ that forms stable protofibrils and here we use solid-state NMR spectroscopy and molecular modeling to derive a structural model of these. NMR data are consistent with packing of residues 16 to 42 of Aβ protomers into hexameric barrel-like oligomers within the protofibril. The core of the oligomers consists of all residues of the central and C-terminal hydrophobic regions of Aβ, and hairpin loops extend from the core. The model accounts for why Aβ42 forms oligomers and protofibrils more easily than Aβ40 .
寡聚体和原纤维状聚集物由淀粉样蛋白-β肽（Aβ）形成，被认为与阿尔茨海默病的病理学有关。阿尔茨海默病病理学的核心还在于，较长的 Aβ42 肽比更常见的 Aβ40 更易于聚集。详细的 Aβ 寡聚体和原纤维结构研究受到聚集物异质性和不稳定性的阻碍。我们之前设计了一种能够形成稳定原纤维的 Aβ 变体，在这里我们使用固态 NMR 光谱和分子建模来推导出这些原纤维的结构模型。NMR 数据与 Aβ 原纤维内 16 至 42 位残基的六聚体桶状寡聚体的包装一致。寡聚体的核心由 Aβ 中心和 C 末端疏水区的所有残基组成，发夹环从核心延伸。该模型解释了为什么 Aβ42 比 Aβ40 更容易形成寡聚体和原纤维。
