Differential effects of synaptic and extrasynaptic NMDA receptors on Aß-induced nitric oxide production in cerebrocortical neurons.
J Neurosci
; 34(14): 5023-8, 2014 Apr 02.
Article
em En
| MEDLINE
| ID: mdl-24695719
ABSTRACT
Oligomerized amyloid-ß (Aß) 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 Aß 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 Aß1-42 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 Aß-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 Aß 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 Aß-induced synaptic damage. These results suggest that pharmacological intervention specifically aimed at eNMDARs may decrease Aß-induced nitrosative stress and thus ameliorate neurotoxic damage to synapses.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Córtex Cerebelar
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Peptídeos beta-Amiloides
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Receptores de N-Metil-D-Aspartato
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Neurônios
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Óxido Nítrico
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Neurosci
Ano de publicação:
2014
Tipo de documento:
Article