Differential effects of synaptic and extrasynaptic NMDA receptors on Aβ-induced nitric oxide production in cerebrocortical neurons.
Oligomerized amyloid-β (Aβ) 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 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. Here, using rat primary cerebrocortical cultures, we demonstrate that Aβ1-42 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 Aβ-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 Aβ 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 Aβ-induced synaptic damage. These results suggest that pharmacological intervention specifically aimed at eNMDARs may decrease Aβ-induced nitrosative stress and thus ameliorate neurotoxic damage to synapses.
Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
Elena
E
Molokanova
Mohd Waseem
MW
Akhtar
Sara
S
Sanz-Blasco
Shichun
S
Tu
Juan C
JC
Piña-Crespo
Scott R
SR
McKercher
Stuart A
SA
Lipton
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013997:Time Factors
C503301:4-amino-5-methylamino-2',7'-difluorofluorescein diacetate; D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005452:Fluoresceins; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester
NMDA receptor; amyloid-β; extrasynaptic; nitric oxide; synaptic