Beta-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) (beta A(25-35)) on [(3)H]-glutamate uptake on cortical neuron or astrocyte cultures in comparison with a scrambled peptide (SCR) and dihydrokainic acid (DHK), a prototypic uptake inhibitor. beta A(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, beta A(25-35) dose-dependently (0.5-15 microM) increased glutamate levels in media from neuron cultures. DHK only enhanced extracellular glutamate at the highest concentration tested (2500 microM). beta A(25-35) induced gradual neurotoxicity (0.1-50 microM) over time. Exposure to beta A(25-35) resulted in increased uptake in astrocytes (0.25-5 microM) and neurons (0.5-15 microM) surviving its toxic effects. However, exposure to DHK (2.5-2500 microM) did not induce neurotoxicity nor modulated uptake. These results indicate that, while inhibition of glutamate uptake may be involved in the neurotoxic effects of beta A(25-35), enhancement of uptake may be a survival mechanism following exposure to beta A(25-35).
Fernández-Tomé
Paz
P
Institute of Pharmacology and Toxicology, CSIC, Faculty of Medicine, Complutense University, Madrid, Spain.
Brera
Begoña
B
Arévalo
María-Angeles
MA
de Ceballos
María L
ML
D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats
D027322:Amino Acid Transport System X-AG; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C074636:amyloid beta-protein (25-35); D018698:Glutamic Acid; C020889:dihydrokainic acid; D007608:Kainic Acid