Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
J Am Chem Soc. 2011 May 4;133(17):6505-8. doi: 10.1021/ja1117123. Epub 2011 Apr 12.
A critical aspect to understanding the molecular basis of Alzheimer's disease (AD) is the characterization of the kinetics of interconversion between the different species present during amyloid-β protein (Aβ) aggregation. By monitoring hydrogen/deuterium exchange in Aβ fibrils using electrospray ionization mass spectrometry, we demonstrate that the Aβ molecules comprising the fibril continuously dissociate and reassociate, resulting in molecular recycling within the fibril population. Investigations on Aβ40 and Aβ42 amyloid fibrils reveal that molecules making up Aβ40 fibrils recycle to a much greater extent than those of Aβ42. By examining factors that could influence molecular recycling and by running simulations, we show that the rate constant for dissociation of molecules from the fibril (k(off)) is much greater for Aβ40 than that for Aβ42. Importantly, the k(off) values obtained for Aβ40 and Aβ42 reveal that recycling occurs on biologically relevant time scales. These results have implications for understanding the role of Aβ fibrils in neurotoxicity and for designing therapeutic strategies against AD.
理解阿尔茨海默病（AD）分子基础的一个关键方面是对不同种淀粉样β蛋白（Aβ）聚集物之间的转化动力学进行特征描述。通过使用电喷雾电离质谱监测 Aβ 原纤维中的氢/氘交换，我们证明了构成原纤维的 Aβ 分子不断地解离和再组装，导致原纤维群体中的分子循环。对 Aβ40 和 Aβ42 淀粉样原纤维的研究表明，Aβ40 原纤维中组成分子的循环程度比 Aβ42 大得多。通过研究可能影响分子循环的因素并进行模拟，我们表明 Aβ40 从原纤维解离的速率常数（k(off)）比 Aβ42 大得多。重要的是，Aβ40 和 Aβ42 的 k(off)值表明循环发生在具有生物学相关性的时间尺度上。这些结果对于理解 Aβ 原纤维在神经毒性中的作用以及设计针对 AD 的治疗策略具有重要意义。
