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J. Biol. Chem., Vol. 280, Issue 43, 35789-35792, October 28, 2005

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Hydrogen Peroxide Is Generated during the Very Early Stages of Aggregation of the Amyloid Peptides Implicated in Alzheimer Disease and Familial British Dementia^*

Brian J. Tabner1, Omar M. A. El-Agnaf¶1, Stuart Turnbull, Matthew J. German||, Katerina E. Paleologou, Yoshihito Hayashi, Leanne J. Cooper, Nigel J. Fullwood, and David Allsop2

From the Magnetic Resonance Laboratory, Department of Biological Sciences, and ^||Department of Physics, Lancaster University, Lancaster, LA1 4YQ, United Kingdom and ^¶Department of Biochemistry, Faculty of Medicine and Health Science, United Arab Emirates University, Al-Ain, United Arab Emirates

Alzheimer disease and familial British dementia are neurodegenerative diseases that are characterized by the presence of numerous amyloid plaques in the brain. These lesions contain fibrillar deposits of the -amyloid peptide (A) and the British dementia peptide (ABri), respectively. Both peptides are toxic to cells in culture, and there is increasing evidence that early "soluble oligomers" are the toxic entity rather than mature amyloid fibrils. The molecular mechanisms responsible for this toxicity are not clear, but in the case of A, one prominent hypothesis is that the peptide can induce oxidative damage via the formation of hydrogen peroxide. We have developed a reliable method, employing electron spin resonance spectroscopy in conjunction with the spin-trapping technique, to detect any hydrogen peroxide generated during the incubation of A and other amyloidogenic peptides. Here, we monitored levels of hydrogen peroxide accumulation during different stages of aggregation of A-(1–40) and ABri and found that in both cases it was generated as a short "burst" early on in the aggregation process. Ultrastructural studies with both peptides revealed that structures resembling "soluble oligomers" or "protofibrils" were present during this early phase of hydrogen peroxide formation. Mature amyloid fibrils derived from A-(1–40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases.

Received for publication, June 7, 2005 , and in revised form, August 30, 2005.

^* This research was supported by Project Grant GR065764AIA from The Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These two authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 44 1524 592122; Fax: 44 1524 593192; E-mail: d.allsop{at}lancaster.ac.uk.

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