The extracellular signal-regulated kinase cascade suppresses amyloid β protein-induced promotion of glutamate clearance in cultured rat cortical astrocytes

We have recently found that Alzheimer's disease amyloid beta protein (Abeta) activates the extracellular signal-regulated kinase (ERK) and promotes L-glutamate uptake in astrocytes. To elucidate the relationship between the Abeta-induced ERK phosphorylation and promotion of L-glutamate uptake, we investigated the effects of U0126 and PD98059, specific inhibitors of the ERK-activating enzyme MEK, in cultured rat cortical astrocytes. Abeta-induced ERK phosphorylation was completely blocked by the MEK inhibitors, while Abeta-induced promotion of extracellular L-glutamate clearance was enhanced by the presence of the MEK inhibitors. Abeta-induced increase of the glutamate transporter GLAST expression was also enhanced by the presence of MEK inhibitors. The effective concentrations of MEK inhibitors in enhancing Abeta-induced promotion of glutamate clearance and GLAST expression were consistent with those in blocking Abeta-induced ERK phosphorylation. These results suggest that the MEK/ERK signal functions to suppress Abeta-induced upregulation of a glutamate uptake system in astrocytes. @ 2003 Elsevier B.V. All rights reserved.