Promotion of transition metal-induced reactive oxygen species formation by beta-amyloid.
beta-amyloid protein appears to be involved in the neural degeneration associated with Alzheimer's disease. However, its mechanism of action is poorly understood. The ability of the neurotoxic peptide fragment (25-35) derived from beta-amyloid, to promote the generation of reactive oxygen species (ROS) by a postmitochondrial fraction (P2) derived from rat cerebrocortex, has been examined. The peptide fragment, when incubated together with P2, did not cause excess ROS formation. However, 10 microM FeSO4 or 10 microM CuSO4 were able to enhance ROS production in the P2 fraction and this was increased further in the concurrent presence of the 25-35 fragment. The corresponding inverse sequence non-neurotoxic peptide (35-25) had no parallel ability to augment iron-stimulated ROS production suggesting a degree of specificity for the observed effect. There was no formation of excess ROS when the 25-35 peptide and 0.5 mM Al2(SO4)3 were incubated with the P2 fraction. However in the presence of both aluminum and iron salts together with the 25-35 peptide, ROS production was augmented to a level significantly higher than that in the absence of aluminum. Polyglutamate, a peptide reported to mitigate aluminum toxicity had no effect on iron-related ROS generation but completely prevented its further potentiation by aluminum. The results indicate that beta-amyloid is able to potentiate the free-radical promoting capacity of metal ions such as iron, copper and aluminum. Such potentiation may be a relevant mechanism underlying beta-amyloid-induced degeneration of nerve cells.
Center for Occupational and Environmental Health, Department of Community and Environmental Medicine, University of California Irvine, Irvine, CA 92697-1820, USA.
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D000534:Alum Compounds / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D019327:Copper Sulfate / Q000494:pharmacology*; D004357:Drug Synergism; D005296:Ferrous Compounds / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000534:Alum Compounds; D016229:Amyloid beta-Peptides; D005296:Ferrous Compounds; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C074636:amyloid beta-protein (25-35); C041524:aluminum sulfate; C020748:ferrous sulfate; D005978:Glutathione; D019327:Copper Sulfate