AMYLOID BETA-MEDIATED OXIDATIVE AND METABOLIC STRESS IN RAT CORTICAL-NEURONS - NO DIRECT EVIDENCE FOR A ROLE FOR H2O2 GENERATION

H2O2 and free radical-mediated oxidative stresses have been implicated in mediating amyloid beta(1-40) [A beta(1-40)] neurotoxicity to cultu red neurons. In this study, we confirm that addition of the H2O2-scave nging enzyme catalase protects neurons in culture against A beta-media ted toxicity; however, it does so by a mechanism that does not involve its ability to scavenge H2O2. A beta-mediated elevation in intracellu lar H2O2 production is suppressed by addition of a potent H2O2 scaveng er without any significant neuroprotection. Three intracellular bioche mical markers of H2O2-mediated oxidative stress were unchanged by A be ta treatment: (a) glyceraldehyde-3-phosphate dehydrogenase activity, ( b) hexose monophosphate shunt activity, and (c) glucose oxidation via the tricarboxylic acid cycle. Ionspray mass spectra of A beta in the i ncubation medium indicated that A beta itself is an unlikely source of reactive oxygen species. In this study we demonstrate that intracellu lar ATP concentration is compromised during the first 24-h exposure of neurons to A beta. Our results challenge a pivotal role for H2O2 gene ration in mediating A beta toxicity, and we suggest that impairment of energy homeostasis may be a more significant early factor in the neur odegenerative process.