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There is growing evidence for alterations in iron and copper homeostasis during aging that are exacerbated in neurodegenerative diseases such as Alzheimer's disease (AD). However, how iron and copper accumulation leads to nerve cell damage in AD is not clear. In order to better understand how iron and copper can contribute to nerve cell death, a simple, well-defined in vitro model of cell death, the oyxtosis assay, was used. This assay uses glutamate to induce glutathione (GSH) depletion which initiates a form of oxidative stress-induced programmed cell death. A reduction in GSH is seen in the aging brain, is associated with cognitive dysfunction and is accelerated in many CNS diseases including AD. It is shown that both iron and copper potentiate both GSH loss and cell death in this model. Iron and copper also potentiate cell death induced by other GSH depleters but not by compounds that induce oxidative stress via other pathways. At least part of the effects of copper on GSH are related to its ability to reduce the activity of glutamate cysteine ligase, the rate limiting enzyme in GSH synthesis. Both metals also alter several signaling pathways involved in modulating nerve cell death. Together, these results suggest that in vivo iron and copper may specifically enhance nerve cell death under conditions where GSH levels are reduced.Iron and copper potentiate the toxicity of stresses that induce glutathione loss.Neither iron nor copper promote cell death induced by H2O2 or tert-butyl peroxide.Both iron and copper increase intracellular levels of ROS and lipid peroxidation.Copper but not iron reduces glutamate cysteine ligase activity.Both iron and copper reduce Akt activation and increase JNK activation.