title: Beta-amyloid neurotoxicity in vitro: evidence of oxidative stress but not protection by antioxidants.
abstract: Recent data from several groups suggest that the primary mechanism of beta-amyloid neurotoxicity may be mediated by reactive oxygen species. To evaluate this hypothesis, we first compared the efficacy of antioxidant agents in preventing toxicity caused by oxidative insults (iron, hydrogen peroxide, and tert-butyl hydroperoxide) and beta-amyloid peptides in cultured rat hippocampal neurons. Tested antioxidants (propyl gallate, Trolox, probucol, and promethazine) generally provided significant protection against oxidative insults but not beta-amyloid peptides. Next, we examined whether beta-amyloid causes oxidative stress, by comparing levels of lipid peroxidation after exposure to either iron or beta-amyloid. In a cell-free system, iron but not beta-amyloid generated lipid peroxidation. In culture, both insults caused rapid increases in lipid peroxidation, with iron inducing higher levels at later time points. Pretreatment with the antioxidant probucol significantly reduced lipid peroxidation caused by both insults but only attenuated iron toxicity, suggesting that lipid peroxidation does not contribute directly to cell death induced by beta-amyloid. Finally, we observed that increasing basal levels of oxidative stress by pretreating cultures with subtoxic doses of iron significantly increased neuronal vulnerability to beta-amyloid. The ability of beta-amyloid to induce oxidative stress and the demonstration that oxidative stress potentiates beta-amyloid toxicity support the clinical use of antioxidants for AD. However, these data do not support the theory that the primary mechanism of beta-amyloid toxicity involves oxidative pathways, indicating a continued need to identify additional cellular responses to beta-amyloid that underlie its neurodegenerative actions.
authors.affiliation: Institute for Brain Aging and Dementia, University of California Irvine, 92697-4540, U.S.A.
authors.forename: C J
authors.initials: CJ
authors.lastname: Pike
authors.forename: N
authors.initials: N
authors.lastname: Ramezan-Arab
authors.forename: C W
authors.initials: CW
authors.lastname: Cotman
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D007501:Iron / Q000494:pharmacology; D008054:Lipid Peroxides / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats / Q000196:embryology
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D008054:Lipid Peroxides; D009498:Neurotoxins; D007501:Iron