Abstract

The effects of glutamate receptor antagonists on the toxicity of the beta -amyloid peptide (A beta (1-42)) in embryonic chick retina were investigated. When used alo ne or in combination, the N-methyl-D-asparate antagonist, MK-801, the (+/-)-alpha amino-3-hydroxyl-5-methylisoxazole-4-propinic acid/kainate antagonist, DNQX, and the metabotropic receptor antagonist, (RS)1-aminoindan-1,5-dicarboxylic acid, blocked the neurotoxicity of A beta (1-42) Aggregation of A beta (1-42) was significantly increased in the presence of acidic glutamate solutions, but not in the presence of other neurotransmitters. These results point to a dual role of glutamatergic transmission in Alzheimer's disease (AD): (i) A beta neurotoxicity requires activation of glutamate receptors and its blockade prevents cell death; Iii] high concentrations of glutamate in the synaptic cleft indirectly enhance A beta aggregation through acidification of the medium, resulting in increased amounts of neurotoxic amyloid fibrils. These results suggest that glutamatergic neurotransmission may represent a novel target for therapeutic approaches in AD. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.