Economou Nicholas J, Giammona Maxwell J, Do Thanh D, Zheng Xueyun, Teplow David B, Buratto Steven K, Bowers Michael T
Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
Department of Neurology, David Geffen School of Medicine at UCLA; Mary S. Easton Center for Alzheimer's Disease Research at UCLA; and Brain Research Institute and Molecular Biology Institute, University of California , 635 Charles Young Drive South, Los Angeles, California 90095, United States.
J Am Chem Soc. 2016 Feb 17;138(6):1772-5. doi: 10.1021/jacs.5b11913. Epub 2016 Feb 4.
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 a 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 preprotofibrillar β-sheet structures. The preprotofibrils 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 preprotofibril 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.
有证据表明，淀粉样β蛋白（Aβ）42个残基形式的寡聚体，即Aβ42，在阿尔茨海默病（AD）的病因学中起关键作用。在此，我们使用高分辨率原子力显微镜直接成像Aβ42小寡聚体群体，这些寡聚体出现在聚集的最早阶段。我们观察到可归因于单体和相对较小寡聚体的特征，包括二聚体、六聚体和十二聚体。我们发现，即使在低浓度（1μM）和短孵育时间（5分钟）下，Aβ42六聚体和十二聚体在肽溶解后很快成为主要的寡聚体。不久之后（≥10分钟），观察到十二聚体引发延伸的线性前原纤维β折叠结构的形成。前原纤维高度为单个Aβ42层，长度可延伸数百纳米。据我们所知，这是此类结构的首次报道。在每种情况下，前原纤维都偏心地与单层十二聚体相关联。原纤维的形成在更长时间内持续，但伴随着大的球状聚集体的形成。相比之下，Aβ40不会显著形成六聚体或十二聚体，而是产生较小寡聚体的混合物。这些物质导致形成分支链状网络而非离散结构。
