β-Amyloid25-35 inhibits glutamate uptake in cultured neurons and astrocytes:: modulation of uptake as a survival mechanism

Glutamate transporters are vulnerable to oxidants resulting in reduced uptake function. We have studied the effects of beta-amyloid(25-35) (betaA(25-35)) on [H-3]-glutamate uptake on cortical neuron or astrocyte cultures in comparison with a scrambled peptide (SCR) and dihydrokainic acid (DHK), a prototypic uptake inhibitor. betaA(25-35) was more potent than DHK in inhibiting glutamate uptake and the effects of both were more marked on astrocytes than on neurons. At 24 h, betaA(25-35) dose-dependently (0.5-15 muM) increased glutamate levels in media from neuron cultures. DHK only enhanced extracellular glutamate at the highest concentration tested (2500 muM). betaA(25-35) induced gradual neurotoxicity. (0.1-50 muM) over time. Exposure to betaA(25-35) resulted in increased uptake in astrocytes (0.25-5 muM) and neurons (0.5-15 muM) surviving its toxic effects. However, exposure to DHK (2.5-2500 muM) did not induce neurotoxicity nor modulated uptake. These results indicate that, while inhibition of glutamate uptake may be involved in the neurotoxic effects of betaA(25-35), enhancement of uptake may be a survival mechanism following exposure to betaA(25-35). (C) 2004 Elsevier Inc. All rights reserved.