The A Peptide of Alzheimer's Disease Directly Produces Hydrogen Peroxide through Metal Ion Reduction
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- 作者：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.
- 刊名：Biochemistry
- 出版年：1999
- 出版时间：June 15, 1999
- 年：1999
- 卷：38
- 期：24
- 页码：7609 - 7616
- 全文大小：97K
- 年卷期：v.38,no.24(June 15, 1999)
- ISSN：1520-4995
文摘
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 (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 Apeptide 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 H2O2 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 A1-42 
A1-40 > rat A1-40, 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.
peptides has been linked to peroxidegeneration in cell cultures by an unknown mechanism. We now show that human A directly produceshydrogen 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 Apeptide 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 H2O2 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 A1-42 A1-40 > rat A1-40, 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.