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.