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

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.

[1]  Michael J. Devine,et al.  Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease , 2016, Antioxidants & redox signaling.

[2]  S. Drew.  The N Terminus of α-Synuclein Forms Cu(II)-Bridged Oligomers. , 2015, Chemistry.

[3]  C. Dobson,et al.  Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation , 2015, Proceedings of the National Academy of Sciences.

[4]  L. Bubacco,et al.  Differences in the binding of copper(I) to α- and β-synuclein. , 2015, Inorganic chemistry.

[5]  A. Bush,et al.  Biological metals and metal-targeting compounds in major neurodegenerative diseases. , 2014, Chemical Society reviews.

[6]  J. Baum,et al.  A revised picture of the Cu(II)-α-synuclein complex: the role of N-terminal acetylation. , 2014, Biochemistry.

[7]  F. Nepveu,et al.  The catalytically active copper-amyloid-Beta state: coordination site responsible for reactive oxygen species production. , 2013, Angewandte Chemie.

[8]  K. Warncke,et al.  Local structure and global patterning of Cu2+ binding in fibrillar amyloid-β [Aβ(1-40)] protein. , 2012, Journal of the American Chemical Society.

[9]  C. Hureau,et al.  Coordination of redox active metal ions to the amyloid precursor protein and to amyloid-β peptides involved in Alzheimer disease. Part 1: An overview , 2012 .

[10]  Christopher M. Dobson,et al.  Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein , 2012, Cell.

[11]  R. Reiter,et al.  Accumulation of Exogenous Amyloid-Beta Peptide in Hippocampal Mitochondria Causes Their Dysfunction: A Protective Role for Melatonin , 2012, Oxidative medicine and cellular longevity.

[12]  N. Heegaard,et al.  Cu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β Peptides* , 2011, The Journal of Biological Chemistry.

[13]  Ruth Nussinov,et al.  Molecular-level examination of Cu2+ binding structure for amyloid fibrils of 40-residue Alzheimer's β by solid-state NMR spectroscopy. , 2011, Journal of the American Chemical Society.

[14]  E. Walter,et al.  Coordination features and affinity of the Cu²+ site in the α-synuclein protein of Parkinson's disease. , 2011, Biochemistry.

[15]  F. Marken,et al.  The synucleins are a family of redox-active copper binding proteins. , 2011, Biochemistry.

[16]  J. Savéant,et al.  Electrochemical and homogeneous electron transfers to the Alzheimer amyloid-β copper complex follow a preorganization mechanism , 2010, Proceedings of the National Academy of Sciences.

[17]  B. Fischer,et al.  Abeta40, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems. , 2009, Biochemistry.

[18]  J. H. Viles,et al.  Amyloid beta-Cu2+ complexes in both monomeric and fibrillar forms do not generate H2O2 catalytically but quench hydroxyl radicals. , 2008, Biochemistry.

[19]  C. Griesinger,et al.  Site-specific interactions of Cu(II) with alpha and beta-synuclein: bridging the molecular gap between metal binding and aggregation. , 2008, Journal of the American Chemical Society.

[20]  C. Masters,et al.  Cu2+ binding modes of recombinant alpha-synuclein--insights from EPR spectroscopy. , 2008, Journal of the American Chemical Society.

[21]  Ashley I Bush,et al.  Metals in Alzheimer's and Parkinson's diseases. , 2008, Current opinion in chemical biology.

[22]  P. Faller,et al.  Redox Chemistry of Copper–Amyloid‐β: The Generation of Hydroxyl Radical in the Presence of Ascorbate is Linked to Redox‐Potentials and Aggregation State , 2007, Chembiochem : a European journal of chemical biology.

[23]  C. Dobson,et al.  Protein misfolding, functional amyloid, and human disease. , 2006, Annual review of biochemistry.

[24]  L. Łankiewicz,et al.  Products of Cu(II)-catalyzed oxidation in the presence of hydrogen peroxide of the 1-10, 1-16 fragments of human and mouse beta-amyloid peptide. , 2004, Journal of inorganic biochemistry.

[25]  C. Schöneich,et al.  Cu(II)-catalyzed oxidation of beta-amyloid peptide targets His13 and His14 over His6: Detection of 2-Oxo-histidine by HPLC-MS/MS. , 2002, Chemical research in toxicology.

[26]  D. Allsop,et al.  alpha-Synuclein implicated in Parkinson's disease catalyses the formation of hydrogen peroxide in vitro. , 2001, Free radical biology & medicine.

[27]  T. Montine,et al.  Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. , 1999, The American journal of pathology.

[28]  J. D. Robertson,et al.  Copper, iron and zinc in Alzheimer's disease senile plaques , 1998, Journal of the Neurological Sciences.

[29]  Peter Riederer,et al.  Transition Metals, Ferritin, Glutathione, and Ascorbic Acid in Parkinsonian Brains , 1989, Journal of neurochemistry.

[30]  C. Marsden,et al.  Basal Lipid Peroxidation in Substantia Nigra Is Increased in Parkinson's Disease , 1989, Journal of neurochemistry.

[31]  D. Butterfield,et al.  Role of oxidative stress in the progression of Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[32]  G. Perry,et al.  Sequestration of iron by Lewy bodies in Parkinson’s disease , 2000, Acta Neuropathologica.