title: Amyloid beta peptides do not form peptide-derived free radicals spontaneously, but can enhance metal-catalyzed oxidation of hydroxylamines to nitroxides.
abstract: Amyloid beta (Abeta) peptides play an important role in the pathogenesis of Alzheimer's disease. Free radical generation by Abeta peptides was suggested to be a key mechanism of their neurotoxicity. Reports that neurotoxic free radicals derived from Abeta-(1-40) and Abeta-(25-35) peptides react with the spin trap N-tert-butyl-alpha-phenylnitrone (PBN) to form a PBN/.Abeta peptide radical adduct with a specific triplet ESR signal assert that the peptide itself was the source of free radicals. We now report that three Abeta peptides, Abeta-(1-40), Abeta-(25-35), and Abeta-(40-1), do not yield radical adducts with PBN from the Oklahoma Medical Research Foundation (OMRF). In contrast to OMRF PBN, incubation of Sigma PBN in phosphate buffer without Abeta peptides produced a three-line ESR spectrum. It was shown that this nitroxide is di-tert-butylnitroxide and is formed in the Sigma PBN solution as a result of transition metal-catalyzed auto-oxidation of the respective hydroxylamine present as an impurity in the Sigma PBN. Under some conditions, incubation of PBN from Sigma with Abeta-(1-40) or Abeta-(25-35) can stimulate the formation of di-tert-butylnitroxide. It was shown that Abeta peptides enhanced oxidation of cyclic hydroxylamine 1-hydroxy-4-oxo-2,2,6, 6-tetramethylpiperidine (TEMPONE-H), which was strongly inhibited by the treatment of phosphate buffer with Chelex-100. It was shown that ferric and cupric ions are effective oxidants of TEMPONE-H. The data obtained allow us to conclude that under some conditions toxic Abeta peptides Abeta-(1-40) and Abeta-(25-35) enhance metal-catalyzed oxidation of hydroxylamine derivatives, but do not spontaneously form peptide-derived free radicals.
authors: Laboratory of Pharmacology and Chemistry, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. dikalov@niehs.gov
authors: S I
authors: SI
authors: Dikalov
authors: M P
authors: MP
authors: Vitek
authors: K R
authors: KR
authors: Maples
authors: R P
authors: RP
authors: Mason
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002073:Butanes; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000378:metabolism; D003497:Cyclic N-Oxides; D005290:Ferric Compounds / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006898:Hydroxylamines / Q000378:metabolism*; D008670:Metals / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000378:metabolism*; D010084:Oxidation-Reduction; D010880:Piperidines; D013113:Spin Labels
chemical_list: D016229:Amyloid beta-Peptides; D002073:Butanes; D003497:Cyclic N-Oxides; D005290:Ferric Compounds; D005609:Free Radicals; D006898:Hydroxylamines; D008670:Metals; D009589:Nitrogen Oxides; D010880:Piperidines; D013113:Spin Labels; C007539:di-t-butyl nitroxide; C103674:1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidine; C029217:phenyl-N-tert-butylnitrone; D003300:Copper