40, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems

Rozena Baruch-Suchodolsky, Bilha Fischer

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

The brains of individuals diagnosed with Alzheimer's disease (AD) are characterized by amyloid plaques, of which the major component is Aβ peptide. Excessive Cu and Fe ions binding to Aβ were suggested to have a deleterious effect on promoting both the aggregation of Aβ and the generation of reactive oxygen species (ROS). Other studies suggested that Aβ plays a protective role by acting as an antioxidant at nanomolar concentrations. The apparent confusion regarding the antioxidant and pro-oxidant properties of Aβ40 encouraged us to explore the modulatory role of Aβ40 at the molecular level under oxidative stress conditions. Here, we focused on Aβ40 in the simplest oxidative system, namely, Cu(I)/Cu(II)/Fe(II)-H2O2. Using ESR, we monitored the production of OH radicals in the above-mentioned systems in the presence of Aβ40. We found that Aβ40, 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 IC50 values of 13-62 μM. Aβ40 proved to be 3.8-6.5 and 15-42 times more potent than the soluble Aβ28 and the potent antioxidant Trolox, respectively, in the Cu(I)/Fe(II)-H2O2 systems. Time-dependent enhancement of ROS production by Aβ40 occurs only at low concentrations of aggregated Aβ40 and in the presence of Cu(II). On the basis of the extremely low IC50 values of Aβ40 and the extensive oxidative damage caused to Aβ40 in Cu(I)/Fe (II)-H2O2 systems, we propose that radical scavenging is the major mechanism of antioxidant activity of Aβ40 in addition to metal ion chelation. In summary, Aβ40, 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 Aβ40-Cu(I)/Fe(II) complex per se that is responsible for the oxidative damage in AD.

Original languageEnglish
Pages (from-to)4354-4370
Number of pages17
JournalBiochemistry
Volume48
Issue number20
DOIs
StatePublished - 26 May 2009

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