Metal-dependent generation of reactive oxygen species from amyloid proteins implicated in neurodegenerative disease

Using a method based on ESR spectroscopy and spin-trapping, we have shown that Aβ (amyloid β-peptide) (implicated in Alzheimer's disease), α-synuclein (implicated in Parkinson's disease), ABri (British dementia peptide) (responsible for familial British dementia), certain toxic fragments of the prion protein (implicated in the transmissible spongiform encephalopathies) and the amylin peptide (found in the pancreas in Type 2 diabetes mellitus) all have the common ability to generate H₂O₂in vitro. Numerous controls (reverse, scrambled and non-toxic peptides) lacked this property. We have also noted a positive correlation between the ability of the various proteins tested to generate H₂O₂ and their toxic effects on cultured cells. In the case of Aβ and ABri, we have shown that H₂O₂ is generated as a short burst during the early stages of aggregation and is associated with the presence of protofibrils or oligomers, rather than mature fibrils. H₂O₂ is readily converted into the aggressive hydroxyl radical by Fenton chemistry, and this extremely reactive radical could be responsible for much of the oxidative damage seen in all of the above disorders. We suggest that the formation of a redox-active complex involving the relevant amyloidogenic protein and certain transition-metal ions could play an important role in the pathogenesis of several different protein misfolding disorders.