Amyloid-β and α-Synuclein Decrease the Level of Metal-Catalyzed Reactive Oxygen Species by Radical Scavenging and Redox Silencing

Abstract

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 Cu2+-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 Cu2+ 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 Cu2+ and other ROS-active metal ions in the aggregates or as a downstream consequence of the formation of the pathological amyloid structures.

A Unified View of Assessing the Pro‐oxidant versus Antioxidant Nature of Amyloid Beta Conformers

“…production by these samples compared to the controls indicates that these species act as antioxidants. Our observations are in agreement with reports by Viles, Teilum, and co‐workers and suggest that Aβ monomers and fibrils possess antioxidant activity not because they bind Cu 2+ in a conformation that is unproductive for ROS production, but rather because the peptide itself acts as a sacrificial scavenger of OH . .…”

“…The primary rationale for the antioxidant role is that the level of free radicals produced by Aβ peptides is lower than that of free Cu 2+ in solution; the pro‐oxidant role is based on the observation that Cu–Aβ produces more free radicals than other copper proteins and peptides. Recent in vitro studies have suggested that both the monomeric and fibrillar forms of Aβ act as radical scavengers, and that the Aβ 40 fibrils cause redox silencing, leading to significantly less ROS production than the monomeric Cu–Aβ . Although these studies have provided significant insight into the monomeric and fibrillar forms of the peptide, the contribution of the oligomeric forms of Aβ towards Cu‐catalyzed ROS generation is less well understood.…”

A Trishistidine Pseudopeptide with Ability to Remove Both CuΙ and CuΙΙ from the Amyloid‐β Peptide and to Stop the Associated ROS Formation

“…[45] We have focused our study on the monomeric peptidic complex, because it is the major form responsible for ROS production, fibrillary forms being less active by one order of magnitude. [46] ROS production corresponds to the incomplete reduction of dioxygen by ascorbate catalyzed by the Cu I/II Aβ complex leading to O 2 ° - , H 2 O 2 and HO°. Thus, to probe ROS formation, either ascorbate consumption can be followed by UV-Vis at 265 nm or HO° formation can be monitored by the detection of the fluorescent 7-OH-CCA (7-hydroxy-coumarin-3-carboxylic acid) dye formed by reaction of HO° with the CCA (Coumarin-3-carboxylic acid) molecule.…”

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

“…On the other hand, a recent study showed that the copper/α-syn binding can exert a protective role against ROS. Pedersen et al (2016) found that the levels of ROS and the rate at which they are generated, are significantly reduced when copper is bound to α-syn (and Aβ) particularly when the protein is in oligomeric and fibrillar form. These observations suggest that copper bound to the protein is less accessible to the solvent and therefore less capable of reacting with ascorbate, resulting in a reduced ROS formation, but further studies are necessary to elucidate this issue.…”