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

Abstract

Glutamate transporters are vulnerable to oxidants resulting in reduced uptake function. We have studied the effects of β-amyloid25–35 (βA25–35) on [3H]-glutamate uptake on cortical neuron or astrocyte cultures in comparison with a scrambled peptide (SCR) and dihydrokainic acid (DHK), a prototypic uptake inhibitor. βA25–35 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, βA25–35 dose-dependently (0.5–15 μM) increased glutamate levels in media from neuron cultures. DHK only enhanced extracellular glutamate at the highest concentration tested (2500 μM). βA25–35 induced gradual neurotoxicity (0.1–50 μM) over time. Exposure to βA25–35 resulted in increased uptake in astrocytes (0.25–5 μM) and neurons (0.5–15 μM) surviving its toxic effects. However, exposure to DHK (2.5–2500 μM) did not induce neurotoxicity nor modulated uptake. These results indicate that, while inhibition of glutamate uptake may be involved in the neurotoxic effects of βA25–35, enhancement of uptake may be a survival mechanism following exposure to βA25–35.

Keywords

• Astrocytes
• Alzheimer's disease
• β-Amyloid
• Dihydrokainate
• Glutamate
• Neurons