Key Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education of China, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, China.
Acta Biochim Biophys Sin (Shanghai). 2013 Jul;45(7):570-7. doi: 10.1093/abbs/gmt044. Epub 2013 Jun 6.
It is well known that the aggregation of amyloid-β peptide (Aβ) induced by Cu²⁺ is related to incubation time, solution pH, and temperature. In this work, the aggregation of Aβ₁₋₄₂ in the presence of Cu²⁺ under acidic conditions was studied at different incubation time and temperature (e.g. 25 and 37°C). Incubation temperature, pH, and the presence of Cu²⁺ in Aβ solution were confirmed to alter the morphology of aggregation (fibrils or amorphous aggregates), and the morphology is pivotal for Aβ neurotoxicity and Alzheimer disease (AD) development. The results of atomic force microscopy (AFM) indicated that the formation of Aβ fibrous morphology is preferred at lower pH, but Cu²⁺ induced the formation of amorphous aggregates. The aggregation rate of Aβ was increased with the elevation of temperature. These results were further confirmed by fluorescence spectroscopy and circular dichroism spectroscopy and it was found that the formation of β-sheet structure was inhibited by Cu²⁺ binding to Aβ. The result was consistent with AFM observation and the fibrillation process was restrained. We believe that the local charge state in hydrophilic domain of Aβ may play a dominant role in the aggregate morphology due to the strong steric hindrance. This research will be valuable for understanding of Aβ toxicity in AD.
众所周知，Cu²⁺诱导的淀粉样β肽（Aβ）聚集与孵育时间、溶液 pH 值和温度有关。在这项工作中，研究了在酸性条件下存在 Cu²⁺时 Aβ₁₋₄₂在不同孵育时间和温度（例如 25 和 37°C）下的聚集。孵育温度、pH 值以及 Aβ 溶液中 Cu²⁺的存在被证实会改变聚集的形态（纤维或无定形聚集物），而形态对于 Aβ 的神经毒性和阿尔茨海默病（AD）的发展至关重要。原子力显微镜（AFM）的结果表明，在较低的 pH 值下，Aβ 形成纤维形态的倾向更大，但 Cu²⁺诱导形成无定形聚集物。随着温度的升高，Aβ 的聚集速率增加。荧光光谱和圆二色光谱进一步证实了这一结果，发现 Cu²⁺与 Aβ 结合抑制了β-折叠结构的形成。结果与 AFM 观察一致，纤化过程受到抑制。我们认为，由于强烈的空间位阻，Aβ 亲水域中的局部电荷状态可能在聚集形态中起主导作用。这项研究对于理解 AD 中 Aβ 的毒性很有价值。
