INVESTIGADORES
SANZ BLASCO Sara Isabel
congresos y reuniones científicas
Título:
Differential effects of synaptic and extrasynaptic NMDA receptors on Aβ-induced nitric oxide Production in cerebrocortical neurons
Autor/es:
MOLOKANOVA E; AKHTAR MW; SANZ BLASCO S; NAKAMURA T; OKAMOTO S; TU S; PIÑA-CRESPO JC; MCKERCHER SR; LIPTON SA
Lugar:
San Francisco
Reunión:
Congreso; 58 Biophysical Society Meeting 2014; 2014
Institución organizadora:
Biophysical Society
Resumen:
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 (~75%) 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
AD by decreasing Aβ-induced nitrosative stress and thus ameliorating neurotoxic pathways that damage synapses.