Differential Effects of Synaptic and Extrasynaptic NMDA Receptors on Aβ-Induced Nitric Oxide Production in Cerebrocortical Neurons

Abstract

Oligomerized amyloid-β (Aβ) peptide is thought to contribute to synaptic damage, resulting in dysfunctional neuronal networks in Alzheimer's disease. It has been previously suggested that Aβ may be detrimental to neuronal health, at least in part, by triggering oxidative/nitrosative stress. However, the mechanisms underlying this process remain to be elucidated. In this study, using rat primary cerebrocortical cultures, we investigated how oligomeric Aβ peptides produce nitrosative stress. Relying on different pharmacological inhibitors, we demonstrate that oligomeric Aβ1-42 peptide triggers a dramatic increase in intracellular nitric oxide (NO) concentration via a process mediated by activation of NMDA-type glutamate receptors. Considering that synaptic NMDA receptors (sNMDARs) and extrasynaptic NMDA receptors (eNMDARs) may play disparate or even opposing roles in physiological and pathological events in neurons, we explore their respective roles in oligomeric Aβ-induced increases in intracellular NO levels. Using an established protocol for pharmacological isolation of eNMDARs, we discovered that eNMDARs are responsible for the majority of NO production triggered by the exposure to Aβ oligomers. This effect likely results from the ability of Aβ oligomers to alter the balance of glutamatergic activity between sNMDARs and eNMDARs in neurons, as recently reported by our group. Since sNMDARs outnumber eNMDRs in neurons, eNMDARs appeared to be much more efficient than sNMDARs in stimulating the activity of NOS in response to an Aβ insult. Considering the pronounced role of eNMDARs in neuronal pathophysiology, the effect of this excessive increase in NO could affect various proteins crucial for neuronal and synaptic function and survival. This finding suggests that pharmacological intervention specifically aimed at eNMDARs may provide neuroprotection in Alzheimer's disease by decreasing Aβ-induced nitrosative stress and thus ameliorating neurotoxic pathways that damage synapses.