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

Abstract

We have recently found that Alzheimer’s disease amyloid β protein (Aβ) activates the extracellular signal-regulated kinase (ERK) and promotes l-glutamate uptake in astrocytes. To elucidate the relationship between the Aβ-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. Aβ-induced ERK phosphorylation was completely blocked by the MEK inhibitors, while Aβ-induced promotion of extracellular l-glutamate clearance was enhanced by the presence of the MEK inhibitors. Aβ-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 Aβ-induced promotion of glutamate clearance and GLAST expression were consistent with those in blocking Aβ-induced ERK phosphorylation. These results suggest that the MEK/ERK signal functions to suppress Aβ-induced upregulation of a glutamate uptake system in astrocytes.