Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia.
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 beta-amyloid peptide (Abeta) 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 Abeta, 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 Abeta and other amyloidogenic peptides. Here, we monitored levels of hydrogen peroxide accumulation during different stages of aggregation of Abeta-(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 Abeta-(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.
Tabner
Brian J
BJ
Magnetic Resonance Laboratory, Lancaster University, Lancaster, LA1 4YQ, United Kingdom.
El-Agnaf
Omar M A
OM
Turnbull
Stuart
S
German
Matthew J
MJ
Paleologou
Katerina E
KE
Hayashi
Yoshihito
Y
Cooper
Leanne J
LJ
Fullwood
Nigel J
NJ
Allsop
David
D
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D052160:Benzothiazoles; D003704:Dementia / Q000378:metabolism* / Q000473:pathology*; D004578:Electron Spin Resonance Spectroscopy; D004797:Enzyme-Linked Immunosorbent Assay; D005192:Family Health; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D015233:Models, Statistical; D019636:Neurodegenerative Diseases / Q000473:pathology; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D019097:Spin Trapping; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D006113:United Kingdom
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010446:Peptide Fragments; D010455:Peptides; D013844:Thiazoles; C009462:thioflavin T; D006861:Hydrogen Peroxide; D010100:Oxygen