Web Release Date: May 27,
The A
Peptide of Alzheimer's Disease Directly Produces Hydrogen Peroxide
through Metal Ion Reduction
and
Laboratory for Oxidation Biology, Genetics and Aging Unit, and Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, ZMBH-Center for Molecular Biology, Heidelberg, University of Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany, and Genetics and Aging Unit and Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129
Received February 24, 1999
Revised Manuscript Received April 29, 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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