Oxidative stress markers characterize the neuropathology both of Alzheimer'
s disease and of amyloid-bearing transgenic mice. The neurotoxicity of amyl
oid A beta peptides has been linked to peroxide generation in cell cultures
by an unknown mechanism. We now show that human A beta directly produces h
ydrogen 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 beta peptide reduces Fe
(III) and Cu(II) to Fe(II) and Cu(I), respectively. Spectrochemical techniq
ues are used to show that molecular oxygen is then trapped by A beta and re
duced 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 beta produces a po
sitive thiobarbituric-reactive substance (TEARS) assay, compatible with the
generation of the hydroxyl radical (OH). The amounts of both reduced metal
and TEARS reactivity are greatest when generated by A beta-42 much greater
than A beta 1-40 > rat A beta 1-40, a chemical relationship that correlate
s with the participation of the native peptides in amyloid pathology, These
findings indicate that the accumulation of A beta could be a direct source
of oxidative stress in Alzheimer's disease.