Aβ₄₀, either Soluble or Aggregated, Is a Remarkably Potent Antioxidant in Cell-Free Oxidative Systems

Abstract

The brains of individuals diagnosed with Alzheimer's disease (AD) are characterized by amyloid plaques, of which the major component is Abeta peptide. Excessive Cu and Fe ions binding to Abeta were suggested to have a deleterious effect on promoting both the aggregation of Abeta and the generation of reactive oxygen species (ROS). Other studies suggested that Abeta plays a protective role by acting as an antioxidant at nanomolar concentrations. The apparent confusion regarding the antioxidant and pro-oxidant properties of Abeta(40) encouraged us to explore the modulatory role of Abeta(40) at the molecular level under oxidative stress conditions. Here, we focused on Abeta(40) in the simplest oxidative system, namely, Cu(I)/Cu(II)/Fe(II)-H(2)O(2). Using ESR, we monitored the production of OH radicals in the above-mentioned systems in the presence of Abeta(40). We found that Abeta(40), either in its soluble or in its aggregated form, functioned as a remarkably potent antioxidant in Cu(I)/Fe(II)-catalyzed radical-producing systems and slightly less potently in the presence of Cu(II) with IC(50) values of 13-62 muM. Abeta(40) proved to be 3.8-6.5 and 15-42 times more potent than the soluble Abeta(28) and the potent antioxidant Trolox, respectively, in the Cu(I)/Fe(II)-H(2)O(2) systems. Time-dependent enhancement of ROS production by Abeta(40) occurs only at low concentrations of aggregated Abeta(40) and in the presence of Cu(II). On the basis of the extremely low IC(50) values of Abeta(40) and the extensive oxidative damage caused to Abeta(40) in Cu(I)/Fe(II)-H(2)O(2) systems, we propose that radical scavenging is the major mechanism of antioxidant activity of Abeta(40) in addition to metal ion chelation. In summary, Abeta(40), either soluble or aggregated, at either nanomolar or micromolar concentrations is a highly potent antioxidant in cell-free oxidative systems, acting mainly as a radical scavenger. Therefore, we propose that it is not the Abeta(40)-Cu(I)/Fe(II) complex per se that is responsible for the oxidative damage in AD.

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

“…The sequence of A␤ is highly conserved in species as distantly related as primates (humans) and lobe-finned fishes (Coelacanth) [128] implying that mutations in A␤ are selectively disadvantageous. A␤ has neuroprotective properties [139] and may act variously as an antioxidant [140][141][142][143][144][145], in vascular development [128,146] and function [147], as a regulator of long term potentiation [148] and even as an antimicrobial peptide of the innate immune system [149]. A␤ has also been implicated as a transcription factor.…”

Physiological Role of Amyloid Beta in Neural Cells: The Cellular Trophic Activity

“…Aβ belongs to a group of proteins (metalloproteins) that capture redox metal ions (even under mildly acidotic conditions), thus preventing them from participating in redox cycling with other ligands [45,46]. It has the ability to bind Cu, Fe and Zn [47].…”

Catalytic Activity of Thiacalix[4]arenetetrasulfonate Metal Complexes on Modified Anion-Exchangers for Ascorbic Acid Oxidation

“…This is because free Cu 2+ ion is known to catalyze the decomposition of H 2 O 2 through the Harber-Weiss reaction and/or the Fenton reaction producing • OH. 31) Considering Cu 2+ -TCAS [4] on the anion-exchangers is very stable even in the presence of the excess AsA, no formation of…”