ß-amyloid impairs the regulation of N-methyl-D-aspartate receptors by glycogen synthase kinase 3.
Neurobiol Aging
; 35(3): 449-59, 2014 Mar.
Article
en En
| MEDLINE
| ID: mdl-24094580
Accumulating evidence suggests that glycogen synthase kinase 3 (GSK-3) is a multifunctional kinase implicated in Alzheimer's disease (AD). However, the synaptic actions of GSK-3 in AD conditions are largely unknown. In this study, we examined the impact of GSK-3 on N-methyl-D-aspartate receptor (NMDAR) channels, the major mediator of synaptic plasticity. Application of GSK-3 inhibitors or knockdown of GSK-3 caused a significant reduction of NMDAR-mediated ionic and synaptic current in cortical neurons, whereas this effect of GSK-3 was impaired in cortical neurons treated with ß-amyloid (Aß) or from transgenic mice overexpressing mutant amyloid precursor protein. GSK-3 activity was elevated by Aß, and GSK-3 inhibitors failed to decrease the surface expression of NMDA receptor NR1 (NR1) and NR1/postsynaptic density-95 (PSD-95) interaction in amyloid precursor protein mice, which was associated with the diminished GSK-3 regulation of Rab5 activity that mediates NMDAR internalization. Consequently, GSK-3 inhibitor lost the capability of protecting neurons against N-methyl-D-aspartate-induced excitotoxicity in Aß-treated neurons. These results have provided a novel mechanism underlying the involvement of GSK-3 in AD.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos beta-Amiloides
/
Receptores de N-Metil-D-Aspartato
/
Glucógeno Sintasa Quinasa 3
/
Enfermedad de Alzheimer
/
Neuronas
Límite:
Animals
Idioma:
En
Revista:
Neurobiol Aging
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos