IBCN   20355
INSTITUTO DE BIOLOGIA CELULAR Y NEUROCIENCIA "PROFESOR EDUARDO DE ROBERTIS"
Unidad Ejecutora - UE
artículos
Título:
N-methyl-D aspartate receptors are required for synaptic targeting of Alzheimer´s toxic amiloid-b peptide oligomers
Autor/es:
DECKER HELENA; JÜRGENSEN SOFIA; ADROVER M; BRITO-MOREIRA JORDANO; BOMFIM THERESA; KLEIN WILLIAM; ALBERTO EPSTEIN; DE FELICE FERNANDA; JERUSALINSKY DIANA; FERREIRA SERGIO
Revista:
JOURNAL OF NEUROCHEMISTRY
Editorial:
WILEY-BLACKWELL PUBLISHING, INC
Referencias:
Año: 2010 vol. 114 p. 1520 - 1529
ISSN:
0022-3042
Resumen:
Soluble amyloid-β peptide (Aβ) oligomers, known to accumulate in
Alzheimer's disease brains, target excitatory post-synaptic terminals.
This is thought to trigger synapse deterioration, a mechanism possibly
underlying memory loss in early stage Alzheimer's disease. A major
unknown is the identity of the receptor(s) targeted by oligomers at
synapses. Because oligomers have been shown to interfere with
N-methyl-d-aspartate receptor (NMDAR) function and trafficking, we
hypothesized that NMDARs might be required for oligomer binding to
synapses. An amplicon vector was used to knock-down NMDARs in mature
hippocampal neurons in culture, yielding 90% reduction in dendritic
NMDAR expression and blocking neuronal oxidative stress induced by Aβ
oligomers, a pathological response that has been shown to be mediated by
NMDARs. Remarkably, NMDAR knock-down abolished oligomer binding to
dendrites, indicating that NMDARs are required for synaptic targeting of
oligomers. Nevertheless, oligomers do not appear to bind directly to
NMDARs as indicated by the fact that both oligomer-attacked and
non-attacked neurons exhibit similar surface levels of NMDARs.
Furthermore, pre-treatment of neurons with insulin down-regulates
oligomer-binding sites in the absence of a parallel reduction in surface
levels of NMDARs. Establishing that NMDARs are key components of the
synaptic oligomer binding complex may illuminate the development of
novel approaches to prevent synapse failure triggered by Aβ oligomers.