Amyloid β-Protein Assembly and Alzheimer's Disease: Dodecamers of Aβ42, but Not of Aβ40, Seed Fibril Formation.
Amyloid β-Protein Assembly and Alzheimer's Disease: Dodecamers of Aβ42, but Not of Aβ40, Seed Fibril Formation.
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DOI：
10.1021/jacs.5b11913
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发表时间：
2016-02-17
影响因子：
15
通讯作者：
Bowers MT
中科院分区：
文献类型：
--
作者：
Economou NJ;Giammona MJ;Do TD;Zheng X;Teplow DB;Buratto SK;Bowers MT
有证据表明，β 淀粉样蛋白 (Aβ) 的 42 个残基形式的寡聚体 Aβ42 在阿尔茨海默病 (AD) 的病因学中发挥着关键作用。在这里，我们使用高分辨率原子力显微镜直接对聚集最早阶段发生的 Aβ42 小寡聚体群体进行成像。我们观察到的特征可归因于单体和相对较小的低聚物，包括二聚体、六聚体和十二聚体。我们发现，即使在低浓度（1 μM）和短孵育时间（5 分钟）下，Aβ42 六聚体和十二聚体在肽溶解后也很快成为主要寡聚体。不久后（≥10 分钟），观察到十二聚体播种形成延伸的线性前原纤维 β 折叠结构。前原纤维的高度是单个 Aβ42 层，长度可以延伸数百纳米。据我们所知，这是此类结构的第一份报告。在每种情况下，前原纤维都偏离中心与单层十二聚体相关联。原原纤维的形成持续较长时间，但伴随着大的球状聚集体的形成。相比之下，Aβ40 不会显着形成六聚体或十二聚体，而是产生较小寡聚体的混合物。这些物质导致形成支链状网络而不是离散结构。
Evidence suggests that oligomers of the 42-residue form of the amyloid β-protein (Aβ), Aβ42 play a critical role in the etiology of Alzheimer’s disease (AD). Here we use high resolution atomic force microscopy to directly image populations of small oligomers of Aβ42 that occur at the earliest stages of aggregation. We observe features that can be attributed to monomer and to relatively small oligomers, including dimers, hexamers, and dodecamers. We discovered that Aβ42 hexamers and dodecamers quickly become the dominant oligomers after peptide solubilization, even at low (1 μM) concentrations and short (5 min) incubation times. Soon after (≥10 min), dodecamers are observed to seed the formation of extended, linear pre-protofibrillar β-sheet structures. The pre-protofibrils are a single Aβ42 layer in height and can extend several hundred nanometers in length. To our knowledge this is the first report of structures of this type. In each instance the pre-protofibril is associated off center with a single layer of a dodecamer. Protofibril formation continues at longer times, but is accompanied by the formation of large, globular aggregates. Aβ40, by contrast, does not significantly form the hexamer or dodecamer but instead produces a mixture of smaller oligomers. These species lead to the formation of a branched chain-like network rather than discrete structures.