BETA-AMYLOID PEPTIDE FREE-RADICAL FRAGMENTS INITIATE SYNAPTOSOMAL LIPOPEROXIDATION IN A SEQUENCE-SPECIFIC FASHION - IMPLICATIONS TO ALZHEIMERS-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. (C) 1994 Academic Press, Inc.