β-amyloid impairs the regulation of N-methyl-D-aspartate receptors by glycogen synthase kinase 3.

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 β-amyloid (Aβ) or from transgenic mice overexpressing mutant amyloid precursor protein. GSK-3 activity was elevated by Aβ, 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 Aβ-treated neurons. These results have provided a novel mechanism underlying the involvement of GSK-3 in AD.