beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease.
We have previously reported (Hensley et al., Proc. Natl. Acad. Sci. USA (1994) in press) that beta-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 beta-amyloid, the extremely neurotoxic A beta(25-35) fragment of beta-amyloid peptide produces a detectable radical in minutes. We now report that A beta(25-35) is a potent lipoperoxidation initiator, as inferred from peptide-mediated reduction of nitroxyl stearate spin labels bound to rodent neocortical synaptosomal membranes. A beta(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. A beta(35-25), the non-neurotoxic reverse sequence of A beta(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.
Butterfield
D A
DA
Department of Chemistry, University of Kentucky, Lexington 40506.
Hensley
K
K
Harris
M
M
Mattson
M
M
Carney
J
J
D000544:Alzheimer Disease / Q000209:etiology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003497:Cyclic N-Oxides; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D005849:Gerbillinae; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008959:Models, Neurological; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D013113:Spin Labels; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D003497:Cyclic N-Oxides; D005609:Free Radicals; D010446:Peptide Fragments; D013113:Spin Labels; C037404:12-doxylstearic acid; C005072:5-doxylstearic acid