Dual role of glutamatergic neurotransmission on amyloid beta(1-42) aggregation and neurotoxicity in embryonic avian retina

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, M K-801, the (+/-)-alpha amino-3-hydroxyl-5-methylisoxazole-4-propinic acid/k ainate antagonist, DNQX, and the metabotropic receptor antagonist, (RS)1-am inoindan-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 neurotransmit ters. These results point to a dual role of glutamatergic transmission in A lzheimer's disease (AD): (i) A beta neurotoxicity requires activation of gl utamate receptors and its blockade prevents cell death; Iii] high concentra tions of glutamate in the synaptic cleft indirectly enhance A beta aggregat ion through acidification of the medium, resulting in increased amounts of neurotoxic amyloid fibrils. These results suggest that glutamatergic neurot ransmission may represent a novel target for therapeutic approaches in AD. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.