Institute of Chemical Biology, Imperial College London, London SW7 2AX (UK).
Angew Chem Int Ed Engl. 2015 Jan 19;54(4):1227-30. doi: 10.1002/anie.201408810. Epub 2014 Dec 21.
The kinetics of the interactions between amyloid-β (Aβ) and metal ions are crucial to understanding the physiological and pathological roles of Aβ in the normal brain and in Alzheimer's disease. Using the quenching of a fluorescent probe by Cu(2+), the mechanism of Aβ/Cu(2+) interactions in physiologically relevant conditions has been elucidated. Cu(2+) binds to Aβ at a near diffusion-limited rate, initially forming component I. The switching between component I and II occurs on the second timescale, with a significant energy barrier. Component I is much more reactive towards Cu(2+) ligands and likely responsible for initial Aβ dimer formation. Clioquinol (CQ) is shown to sequester Cu(2+) more effectively than other tested ligands. These findings have implications for the potential roles of Aβ in regulating neurotransmission, and for the screening of small molecules targeting Aβ-metal interactions.
研究表明，在生理相关条件下，淀粉样蛋白-β（Aβ）与金属离子相互作用的动力学对理解 Aβ 在正常大脑和阿尔茨海默病中的生理和病理作用至关重要。使用荧光探针的猝灭来研究 Cu（2+），阐明了 Aβ/Cu（2+）相互作用的机制。Cu（2+）以接近扩散限制的速率与 Aβ结合，最初形成组分 I。组分 I 和 II 之间的切换发生在第二个时间尺度上，存在显著的能量障碍。组分 I 对 Cu（2+）配体的反应性更高，可能负责初始 Aβ 二聚体的形成。研究表明，与其他测试配体相比，氯喹啉（CQ）更有效地螯合 Cu（2+）。这些发现对 Aβ 调节神经递质传递的潜在作用以及针对 Aβ-金属相互作用的小分子筛选具有重要意义。
