Differential effects of synaptic and extrasynaptic NMDA receptors on Aβ-induced nitric oxide production in cerebrocortical neurons.

Oligomerized amyloid-beta (A beta) peptide is thought to contribute to synaptic damage, resulting in dysfunctional neuronal networks in patients with Alzheimer's disease. It has been previously suggested that A beta 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. Here, using rat primary cerebrocortical cultures, we demonstrate that A beta(1-42) oligomers trigger a dramatic increase in intracellular nitric oxide (NO) concentration via a process mediated by activation of NMDA-type glutamate receptors (NMDARs). Considering that synaptic NMDARs and extrasynaptic NMDARs(eNMDARs) can have opposite effects on neuronal viability, we explored their respective roles in A beta-induced increases in NO levels. Surprisingly, after pharmacological isolation of eNMDARs, we discovered that eNMDARs are primarily responsible for the increase in neuronal NO triggered by A beta oligomers. Moreover, we found that the eNMDAR-mediated increase in NO can produce S-nitrosylation of Drp1 (dynamin-related protein 1) and Cdk5 (cyclin-dependent kinase 5), targets known to contribute to A beta-induced synaptic damage. These results suggest that pharmacological intervention specifically aimed at eNMDARs may decrease A beta-induced nitrosative stress and thus ameliorate neurotoxic damage to synapses.