Dual role of glutamatergic neurotransmission on amyloid β 1–42 aggregation and neurotoxicity in embryonic avian retina

Abstract

The effects of glutamate receptor antagonists on the toxicity of the β-amyloid peptide (Aβ 1–42) in embryonic chick retina were investigated. When used alone or in combination, the N-methyl- d-asparate antagonist, MK-801, the (±)-αamino-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 Aβ 1–42. Aggregation of Aβ 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) Aβ neurotoxicity requires activation of glutamate receptors and its blockade prevents cell death; (ii) high concentrations of glutamate in the synaptic cleft indirectly enhance Aβ 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.