The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction.
Oxidative stress markers characterize the neuropathology both of Alzheimer's disease and of amyloid-bearing transgenic mice. The neurotoxicity of amyloid 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 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 beta 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 beta 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 beta 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 A beta 1-42 >> A beta 1-40 > rat A beta 1-40, a chemical relationship that correlates 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.
Huang
X
X
Laboratory for Oxidation Biology, Genetics and Aging Unit, Massachusetts General Hospital, Charlestown 02129, USA.
Atwood
C S
CS
Hartshorn
M A
MA
Multhaup
G
G
Goldstein
L E
LE
Scarpa
R C
RC
Cuajungco
M P
MP
Gray
D N
DN
Lim
J
J
Moir
R D
RD
Tanzi
R E
RE
Bush
A I
AI
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D005290:Ferric Compounds / Q000737:chemistry / Q000378:metabolism; D005296:Ferrous Compounds / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism*; D046911:Macromolecular Substances; D019216:Metals, Heavy / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D013045:Species Specificity; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000737:chemistry
D016229:Amyloid beta-Peptides; D005290:Ferric Compounds; D005296:Ferrous Compounds; D046911:Macromolecular Substances; D019216:Metals, Heavy; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D003300:Copper; D006861:Hydrogen Peroxide