Role of oxidative stress on β-amyloid neurotoxicity elicited during impairment of energy metabolism in the hippocampus: Protection by antioxidants

Age-associated oxidative stress has been implicated in neuronal damage linked with Alzheimer's disease (AD). In addition to the role of β-amyloid peptide (Aβ) in the pathogenesis of AD, reduced glucose oxidative metabolism and decreased mitochondrial activity have been suggested as associated factors. However, the relationship between Aβ toxicity, metabolic impairment, and oxidative stress is far from being understood. In vivo neurotoxicity of Aβ25–35 peptide has been conflicting. However, in previous studies, we have shown that Aβ25–35 consistently induces synaptic toxicity and neuronal death in the hippocampus in vivo, when administered during moderate glycolytic or mitochondrial inhibition. In the present study, we have investigated whether enhancement of Aβ neurotoxicity during these conditions involves oxidative stress. Results show increased lipoperoxidation (LPO) when Aβ is administered in the hippocampus of rats previously treated with the glycolysis inhibitor, iodoacetate. Neuronal damage and LPO are efficiently prevented by vitamin E, while the spin trapper, α-phenyl-N-tert-butyl nitrone, shows partial protection. Aβ stimulates LPO in synaptosomes, but toxicity is only observed in the presence of metabolic inhibitors. Damage and LPO are efficiently prevented by vitamin E. The present results suggest an interaction between oxidative stress and metabolic impairment in the Aβ neurotoxic cascade.