β-Amyloid Peptide Free Radical Fragments Initiate Synaptosomal Lipoperoxidation in a Sequence-Specific Fashion: Implications to Alzheimer′s Disease

D. A. Butterfield, K. Hensley, M. Harris, M. Mattson, J. Carney

Research output: Contribution to journalArticle

Abstract

We have previously reported (Hensley et al., Proc Natl. Acad. Sci USA (1994) in press) that β-amyloid peptide fragments in aqueous media, in a metal-independent reaction, produce reactive peptide free radicals and reactive oxygen species. In contrast to the hours or days necessary to produce neurotoxicity and a detectable free radical for β-amyloid, the extremely neurotoxic Aβ(25-35) fragment of β-amyloid peptide produces a detectable radical in minutes. We now report that Aβ(25-35) is a potent lipoperoxidation initiator, as inferred from peptide-mediated reduction of nitroxyl stearate spin labels bound to rodent neocortical synaptosomal membranes. Aβ(25-35) rapidly quenches the paramagnetism of membrane-bound 12-nitroxyl stearate spin probe deep within the lipid bilayer, but reacts poorly with the 5-nitroxyl isomer whose paramagnetic center is near the lipid/water interface. Aβ(35-25), the non-neurotoxic reverse sequence of Aβ(25-35), shows little proclivity to reduce either spin label. These findings are formulated into a "molecular shrapnel" model of neuronal membrane damage in Alzheimer′s disease.

Original languageEnglish (US)
Pages (from-to)710-715
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume200
Issue number2
DOIs
StatePublished - Apr 30 1994
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Biochemistry

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