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 (Abeta(1-42)) in embryonic chick retina were investigated. When used alone or in combination, the N-methyl-D-asparate antagonist, MK-801, the (+/-)-alphaamino-3-hydroxyl-5-methylisoxazole-4-propionic acid/kainate antagonist, DNQX, and the metabotropic receptor antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid, blocked the neurotoxicity of Abeta(1-42). Aggregation of Abeta(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) Abeta neurotoxicity requires activation of glutamate receptors and its blockade prevents cell death; (ii) high concentrations of glutamate in the synaptic cleft indirectly enhance Abeta 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.
Departamento de Bioquímica Médica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21941-590, Rio de Janeiro, Brazil.
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PR
Louzada
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AC
Paula Lima
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FG
de Mello
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ST
Ferreira
D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000187:drug effects* / Q000494:pharmacology / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D012160:Retina / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D011810:Quinoxalines; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; C056723:FG 9041; D016291:Dizocilpine Maleate