Amyloid-β Decreases Nitric Oxide Production in Cultured Retinal Neurons: A Possible Mechanism for Synaptic Dysfunction in Alzheimer's Disease?

The neurotoxicity of the amyloid-beta peptide (A beta) appears to be, at least in part, related to pathological activation of glutamate receptors by A beta aggregates. However, the downstream signaling pathways leading to neurodegeneration are still incompletely understood. Hyperactivation of nitric oxide synthase (NOS) and increased nitric oxide (NO) production have been implicated in excitotoxic neuronal damage caused by overactivation of glutamate receptors, and it has been suggested that increased NO levels might also play a role in neurotoxicity in Alzheimer's disease. We have examined the effect of blockade of NO production on the neurotoxicity instigated by A beta(42) and by elevated concentrations of glutamate in chick embryo retinal neurons in culture. Results showed that L-nitroarginine methyl ester, a potent inhibitor of all NOS isoforms, had no protective effect against neuronal death induced by either A beta(42) (20 mu M) or glutamate (1 mM). Surprisingly, at short incubation times both A beta and glutamate decreased NO production in retinal neuronal cultures in the absence of neuronal death. Thus, excitotoxic insults induced by A beta and glutamate cause inhibition rather than activation of NO synthase in retinal neurons, suggesting that cell death induced by A beta or glutamate is not related to increased NO production. On the other hand, considering the role of NO in long term potentiation and synaptic plasticity, the decrease in NO levels instigated by A beta and glutamate suggests a possible mechanism leading to synaptic failure in AD.