Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, 106 91, Stockholm, Sweden.
J Biol Inorg Chem. 2014 Jun;19(4-5):623-34. doi: 10.1007/s00775-014-1131-8. Epub 2014 Apr 16.
The amyloid β (Aβ) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditions. Several lines of evidence indicate that the neurotoxic species are the intermediate oligomeric states appearing along the aggregation pathways. This minireview summarizes recent findings, mainly based on solution and solid-state NMR experiments and electron microscopy, which investigate the molecular structures and characteristics of the Aβ peptides at different stages along the aggregation pathways. We conclude that a hairpin-like conformation constitutes a common motif for the Aβ peptides in most of the described structures. There are certain variations in different hairpin conformations, for example regarding H-bonding partners, which could be one reason for the molecular heterogeneity observed in the aggregated systems. Interacting hairpins are the building blocks of the insoluble fibrils, again with variations in how hairpins are organized in the cross-section of the fibril, perpendicular to the fibril axis. The secondary structure propensities can be seen already in peptide monomers in solution. Unfortunately, detailed structural information about the intermediate oligomeric states is presently not available. In the review, special attention is given to metal ion interactions, particularly the binding constants and ligand structures of Aβ complexes with Cu(II) and Zn(II), since these ions affect the aggregation process(es) and are considered to be involved in the molecular mechanisms underlying AD pathology.
β淀粉样蛋白（Aβ）肽是 39-42 个残基长的肽，存在于阿尔茨海默病（AD）患者大脑中的老年斑中。这些肽在水溶液中自组装，从可溶性且主要无结构的单体到不溶性有序纤维。聚集过程强烈受环境条件影响。有几条证据表明，神经毒性物质是沿聚集途径出现的中间寡聚状态。这篇综述总结了最近的发现，主要基于溶液和固态 NMR 实验和电子显微镜，研究了 Aβ 肽在聚集途径不同阶段的分子结构和特性。我们得出结论，发夹样构象构成了大多数描述结构中 Aβ 肽的共同基序。在不同的发夹构象中存在某些变化，例如关于氢键供体，这可能是在聚集系统中观察到的分子异质性的原因之一。相互作用的发夹是不溶性纤维的构建块，同样，在纤维横截面中发夹的组织方式与纤维轴垂直，也存在变化。二级结构倾向在溶液中的肽单体中已经可以看到。不幸的是，目前尚无法获得关于中间寡聚状态的详细结构信息。在综述中，特别关注金属离子相互作用，特别是 Aβ 与 Cu(II)和 Zn(II)的配合物的结合常数和配体结构，因为这些离子影响聚集过程，并被认为参与 AD 病理的分子机制。
