Pedersen Jeppe T, Chen Serene W, Borg Christian B, Ness Samuel, Bahl Justyna M, Heegaard Niels H H, Dobson Christopher M, Hemmingsen Lars, Cremades Nunilo, Teilum Kaare
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Department of Biology, University of Copenhagen , 2200 Copenhagen, Denmark.
J Am Chem Soc. 2016 Mar 30;138(12):3966-9. doi: 10.1021/jacs.5b13577. Epub 2016 Mar 21.
The formation of reactive oxygen species (ROS) is linked to the pathogenesis of neurodegenerative diseases. Here we have investigated the effect of soluble and aggregated amyloid-β (Aβ) and α-synuclein (αS), associated with Alzheimer's and Parkinson's diseases, respectively, on the Cu(2+)-catalyzed formation of ROS in vitro in the presence of a biological reductant. We find that the levels of ROS, and the rate by which ROS is generated, are significantly reduced when Cu(2+) is bound to Aβ or αS, particularly when they are in their oligomeric or fibrillar forms. This effect is attributed to a combination of radical scavenging and redox silencing mechanisms. Our findings suggest that the increase in ROS associated with the accumulation of aggregated Aβ or αS does not result from a particularly ROS-active form of these peptides, but rather from either a local increase of Cu(2+) and other ROS-active metal ions in the aggregates or as a downstream consequence of the formation of the pathological amyloid structures.
活性氧（ROS）的形成与神经退行性疾病的发病机制相关。在此，我们研究了分别与阿尔茨海默病和帕金森病相关的可溶性及聚集态淀粉样β蛋白（Aβ）和α-突触核蛋白（αS），在生物还原剂存在的情况下对体外铜离子（Cu(2+)）催化的ROS形成的影响。我们发现，当Cu(2+)与Aβ或αS结合时，尤其是当它们处于寡聚体或纤维状形式时，ROS的水平以及ROS产生的速率会显著降低。这种效应归因于自由基清除和氧化还原沉默机制的共同作用。我们的研究结果表明，与聚集态Aβ或αS积累相关的ROS增加并非源于这些肽具有特别高ROS活性的形式，而是源于聚集体中Cu(2+)和其他ROS活性金属离子的局部增加，或者是病理性淀粉样结构形成的下游结果。
