BETA-AMYLOID NEUROTOXICITY IN-VITRO - EVIDENCE OF OXIDATIVE STRESS BUT NOT PROTECTION BY ANTIOXIDANTS

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 antiox idant agents in preventing toxicity caused by oxidative insults (iron, hydrogen peroxide, and tert-butyl hydroperoxide) and beta-amyloid pep tides in cultured rat hippocampal neurons. Tested antioxidants (propyl gallate, Trolox, probucol, and promethazine) generally provided signi ficant protection against oxidative insults but not beta-amyloid pepti des, Next, we examined whether beta-amyloid causes oxidative stress, b y comparing revels of lipid peroxidation after exposure to either iron or beta-amyloid. In a cell-free system, iron but not beta-amyloid gen erated lipid peroxidation. In culture, both insults caused rapid incre ases 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 t hat increasing basal levels of oxidative stress by pretreating culture s with subtoxic doses of iron significantly increased neuronal vulnera bility to beta-amyloid. The ability of beta-amyloid to induce oxidativ e stress and the demonstration that oxidative stress potentiates beta- amyloid toxicity support the clinical use of antioxidants for AD. Howe ver, these data do not support the theory that the primary mechanism o f beta-amyloid toxicity involves oxidative pathways, indicating a cont inued need to identify additional cellular responses to beta-amyloid t hat underlie its neurodegenerative actions.