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 Abeta (amyloid beta-peptide) (implicated in Alzheimer's disease), alpha-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 H(2)O(2) in 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 H(2)O(2) and their toxic effects on cultured cells. In the case of Abeta and ABri, we have shown that H(2)O(2) 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. H(2)O(2) 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.
Allsop
David
D
Division of Biomedical and Life Sciences, School of Health and Medicine, Lancaster University, Lancaster, UK. d.allsop@lancaster.ac.uk
Mayes
Jennifer
J
Moore
Susan
S
Masad
Atef
A
Tabner
Brian J
BJ
D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008670:Metals / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010084:Oxidation-Reduction; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000682:Amyloid; D008670:Metals; D017382:Reactive Oxygen Species