Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease


Autoria(s): Hynd, MR; Scott, HL; Dodd, PR
Data(s)

01/01/2004

Resumo

Alzheimer's disease (AD) is the most common form of dementia, accounting for 60-70% of cases in subjects over 65 years of age. Several postulates have been put forward that relate AD neuropathology to intellectual and functional impairment. These range from free-radical-induced damage, through cholinergic dysfunction, to beta-amyloid-induced toxicity. However, therapeutic strategies aimed at improving the cognitive symptoms of patients via choline supplementation, cholinergic stimulation or beta-amyloid vaccination, have largely failed. A growing body of evidence suggests that perturbations in systems using the excitatory amino acid L-glutamate (L-Glu) may underlie the pathogenic mechanisms of (e.g.) hypoxia-ischemia, epilepsy, and chronic neurodegenerative disorders such as Huntington's disease and AD. Almost all neurons in the CNS carry the N-methyl-D-aspartate (NMDA) subtype of ionotropic L-glutamate receptors, which can mediate post-synaptic Ca2+ influx. Excitotoxicity resulting from excessive activation of NMDA receptors may enhance the localized vulnerability of neurons in a manner consistent with AD neuropathology, as a consequence of an altered regional distribution of NMDA receptor subtypes. This review discusses mechanisms for the involvement of the NMDA receptor complex and its interaction with polyamines in the pathogenesis of AD. NMDA receptor antagonists have potential for the therapeutic amelioration of AD. (C) 2004 Elsevier Ltd. All rights reserved.

Identificador

http://espace.library.uq.edu.au/view/UQ:70903

Idioma(s)

eng

Publicador

Pergamon-Elsevier

Palavras-Chave #Biochemistry & Molecular Biology #Neurosciences #Pathogenesis #Human #Cerebral Cortex #Excitotoxicity #Glutamate-receptors #Expression-mrna #Expression-protein #Splice Variants #Polyamines #Methyl-d-aspartate #Nmda Receptor-channel #Voltage-dependent Block #Excitatory Amino-acids #H-3 Mk-801 Binding #Ornithine-decarboxylase Activity #Subunit-specific Potentiation #Cultured Hippocampal-neurons #Messenger-rna Transcripts #Paired Helical Filaments #C1 #320702 Central Nervous System #270201 Gene Expression #730104 Nervous system and disorders #730203 Health related to ageing
Tipo

Journal Article