Xudong Huang, Craig S. Atwood, Mariana A. Hartshorn, Gerd Multhaup, Lee E. Goldstein, Richard C. Scarpa, Math P. Cuajungco, Danielle N. Gray, James Lim, Robert D. Moir, Rudolph E. Tanzi, and Ashley I. Bush.
The A Peptide of Alzheimer's Disease Directly Produces Hydrogen
Peroxide through Metal Ion Reduction, Biochemistry 38(24) :7609 -7616, 1999.
Abstract
Oxidative stress markers characterize the neuropathology both of Alzheimer's disease and of
amyloid-bearing transgenic mice. The neurotoxicity of amyloid A peptides has been linked to
peroxide generation in cell cultures by an unknown mechanism. We now show that human A
directly produces hydrogen peroxide (H2O2) by a mechanism that involves the reduction of metal
ions, Fe(III) or Cu(II), setting up conditions for Fenton-type chemistry. Spectrophotometric
experiments establish that the A peptide reduces Fe(III) and Cu(II) to Fe(II) and Cu(I),
respectively. Spectrochemical techniques are used to show that molecular oxygen is then trapped
by A and reduced to H2O2 in a reaction that is driven by substoichiometric amounts of Fe(II) or
Cu(I). In the presence of Cu(II) or Fe(III), A produces a positive thiobarbituric-reactive
substance (TBARS) assay, compatible with the generation of the hydroxyl radical (OH·). The
amounts of both reduced metal and TBARS reactivity are greatest when generated by A1-42
A1-40 > rat A1-40, a chemical relationship that correlates with the participation of the native
peptides in amyloid pathology. These findings indicate that the accumulation of A could be a
direct source of oxidative stress in Alzheimer's disease.
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