Pii: S0306-4522(99)00036-6

In the present study, we found that amyloid-b peptide enhanced glutamate release from primary cultured rat microglia via the Na-dependent glutamate transporter, which was activated by extracellular K. Glutamate transport current was measured by a conventional whole-cell patch recording mode under voltage-clamp conditions. With the pipette solution containing 10 mM glutamate and 100 mM Na, an increase of the external K concentration from 0 to 10 mM evoked an outward current, resulting from co-extrusion of glutamate and Na. The inward current, reflecting forward glutamate transport, was also activated by external glutamate. Both these reverse and forward glutamate transport currents were three-fold greater in microglia incubated with a relatively low concentration of amyloid-b peptide (25–35) (5 mM) for four days. The glutamate-activated inward current was blocked by d,l-threo-b-hydroxyaspartate in a dose-dependent manner (ranging from 0.001 to 1 mM), but not by a high concentration of kainate (1 mM). The glutamate concentration released from microglia upon high-K stimulation was also significantly increased (up to 170 mM) after treatment with amyloid-b peptide (25–35). These results suggest that, at the pathological sites where extracellular K concentration may increase, the activation of microglia by amyloid-b peptide causes an increase in extracellular glutamate concentration via reverse glutamate transporter, and therefore this mechanism may contribute to the pathogenesis of neuronal dysfunction and death in Alzheimer’s disease. q 1999 IBRO. Published by Elsevier Science Ltd.