Copper and Heme-Mediated Abeta Toxicity: Redox Chemistry, Abeta Oxidations and Anti-ROS Compounds

Abstract

Oxidative stress mediated by reactive oxygen or nitrogen species (ROS/RNS) seems to be implicated in several diseases including neurodegenerative ones. In one of them, namely Alzheimer's disease, there is a large body of evidence that the aggregation of the peptide amyloid-beta (Abeta) is implicated in the generation of the oxidative stress. Redox active metal ions play a key role in oxidative stress, either in the production of ROS/RNS by enzymes or loosely bound metals or in the protection against ROS, mostly as catalytic centers in enzymes. In Alzheimer's disease, it is thought that metals (mostly Cu, Fe and heme) can bind to amyloid-beta and that such systems are involved in the generation of oxidative stress. In the present article, we review the role of ROS/RNS produced by redox active Cu ions and heme compounds in the context of the amyloid cascade. We focus on (i) the coordination chemistry of Cu and heme to Abeta; (ii) the role of the corresponding Abeta adducts in the (catalytic) production of ROS/RNS; (iii) the subsequent degradation of Abeta by these reactive species and (iv) the use of antioxidants, in particular metal sequestering compounds and direct antioxidants like polyphenols as a therapeutic strategies.

Association between copper levels and myocardial infarction: a meta-analysis

“…First, Cu is a transition element that fuels generation of damaging reactive oxygen species if present in normal amounts, and this oxidant damage takes its toll in the later years of life (Gomez-Mendikute & Cajaraville, 2003;Zacharski et al, 2000). The catalytic role of the transition element Cu is considered an important factor in oxidative stress, which plays an important role in the pathogenesis of MI (Chassaing et al, 2012;Giles et al, 1993;Hosseini et al, 2014;Mookerjee et al, 2006). Second, Cu is a powerful catalyst of LDL oxidation in vitro (O'Leary et al, 1992; Patel et al, 1997).…”

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

“…Cu-Ab and Cu-aS are able to catalysethe productiono fROS in the presence of aphysiological reducing agent (e.g.,a scorbate) and dioxygen, ar eaction proposed to contribute to neurodegeneration. [11][12][13] Thus it was proposed that in AD and PD copperi sm isplaced, rathert han ab ulk overloado rb ulk deficiency such as in Wilson's or Menkes diseases. [14] Ab and aS form amyloid-type aggregates under disease conditions througha na utocatalytic self-assembly mechanism.…”

CuII Binding to Various Forms of Amyloid‐β Peptides: Are They Friends or Foes?

“…[14][15][16][17][18] In addition, the redox activity of copper is responsible for the production of reactive oxygen species (ROS) that contribute to the oxidative stress observed in AD. [16,[19][20][21][22][23] Scheme 1. Toxic events in the framework of the amyloid cascade hypothesis: (over)production of the amyloidogenic A peptide, formation of oligomeric species, and ROS production associated with the formation of metal-A complexes.…”

“…Consumption of ascorbate, the most classically used reductant, can be monitored by means of UV/Vis spectroscopy at 265 nm. [22] It is almost impossible to probe the formation of superoxide owing to its high rate of reaction with ascorbate (and reduced ascorbate). Superoxide was detected through the reduction of CytC only when Cu(A ) was reduced by electrolysis.…”

“…[41] There are several tools to detect the formation of hydrogen peroxide, [22] such as the amplex red assay (formation of the resorufin luminophore) and the H 2 DCF assay (formation of 2,7-dichlorofluorescein) as well as the formation of the hydroxyl radical, such as the coumarin-3-carboxylic acid (CCA) assay (formation of the fluorescent 7-OH-CCA adduct) and the thiobarbituric acid reactive substances (TBARS) assay. [22] Scheme 3. Catalytic production of ROS by Cu(A ), from dioxygen and ascorbate as reductant, and some methods to detect the production of the various ROS by means of spectrophotometry.…”