A MODEL FOR BETA-AMYLOID AGGREGATION AND NEUROTOXICITY BASED ON FREE-RADICAL GENERATION BY THE PEPTIDE - RELEVANCE TO ALZHEIMER-DISEASE

Beta-amyloid is a 39- to 43-amino-acid neurotoxic peptide that aggrega tes to form the core of Alzheimer disease-associated senile (amyloid) plaques. No satisfactory hypothesis has yet been proposed to explain t he mechanism of beta-amyloid aggregation and toxicity. We present mass spectrometric and electron paramagnetic resonance spin trapping evide nce that beta-amyloid, in aqueous solution, fragments and generates fr ee radical peptides. Beta-amyloid fragments, at concentrations that pr eviously have been shown to be neurotoxic to cultured neurons, can ina ctivate oxidation-sensitive glutamine synthetase and creatine kinase e nzymes. Also, salicylate hydroxylation assays indicate that reactive o xygen species are generated by the beta-amyloid-(25-35) fragment durin g cell-free incubation. These results are formulated into a free radic al-based unifying hypothesis for neurotoxicity of beta-amyloid and are discussed with reference to membrane molecular alterations in Alzheim er disease.