Oxidative stress markers characterize the neuropathology both of Alzheimer's disease and ofamyloid-bearing transgenic mice. The neurotoxicity of amyloid A
peptides has been linked to peroxidegeneration in cell cultures by an unknown mechanism. We now show that human A
directly produceshydrogen peroxide (H
2O
2) 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 usedto show that molecular oxygen is then trapped by A
and reduced to H
2O
2 in a reaction that is driven bysubstoichiometric amounts of Fe(II) or Cu(I). In the presence of Cu(II) or Fe(III), A
produces a positivethiobarbituric-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 A
1-42
A
1-40 > rat A
1-40, a chemical relationship that correlates with the participation of the nativepeptides in amyloid pathology. These findings indicate that the accumulation of A
could be a directsource of oxidative stress in Alzheimer's disease.