A model for β-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: Relevance to Alzheimer disease

K. Hensley, J. M. Carney, M. P. Mattson, M. Aksenova, M. Harris, J. F. Wu, R. A. Floyd, D. A. Butterfield

Research output: Contribution to journalArticlepeer-review

Abstract

β-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 β- amyloid aggregation and toxicity. We present mass spectrometric and electron paramagnetic resonance spin trapping evidence that β-amyloid, in aqueous solution, fragments and generates free radical peptides. β-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 β-amyloid-(25-35) fragment during cell-free incubation. These results are formulated into a free radical-based unifying hypothesis for neurotoxicity of β-amyloid and are discussed with reference to membrane molecular alterations in Alzheimer disease.

Original languageEnglish (US)
Pages (from-to)3270-3274
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number8
StatePublished - Apr 12 1994
Externally publishedYes

Keywords

  • enzyme inactivation
  • membrane damage
  • oxidative stress
  • peptide fragmentation
  • spin trapping

ASJC Scopus subject areas

  • Genetics
  • General

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