title: A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease.
abstract: beta-Amyloid is a 39- to 43-amino-acid neurotoxic peptide that aggregates to form the core of Alzheimer disease-associated senile (amyloid) plaques. No satisfactory hypothesis has yet been proposed to explain the mechanism of beta-amyloid aggregation and toxicity. We present mass spectrometric and electron paramagnetic resonance spin trapping evidence that beta-amyloid, in aqueous solution, fragments and generates free radical peptides. beta-Amyloid fragments, at concentrations that previously have been shown to be neurotoxic to cultured neurons, can inactivate oxidation-sensitive glutamine synthetase and creatine kinase enzymes. Also, salicylate hydroxylation assays indicate that reactive oxygen species are generated by the beta-amyloid-(25-35) fragment during cell-free incubation. These results are formulated into a free radical-based unifying hypothesis for neurotoxicity of beta-amyloid and are discussed with reference to membrane molecular alterations in Alzheimer disease.
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington 40506.
authors.forename: K
authors.initials: K
authors.lastname: Hensley
authors.forename: J M
authors.initials: JM
authors.lastname: Carney
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
authors.forename: M
authors.initials: M
authors.lastname: Aksenova
authors.forename: M
authors.initials: M
authors.lastname: Harris
authors.forename: J F
authors.initials: JF
authors.lastname: Wu
authors.forename: R A
authors.initials: RA
authors.lastname: Floyd
authors.forename: D A
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D008401:Gas Chromatography-Mass Spectrometry; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry; D012459:Salicylates / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D005609:Free Radicals; D009498:Neurotoxins; D012459:Salicylates