Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease.
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.
Hynd
Matthew R
MR
Department of Biochemistry, University of Queensland, Brisbane 4072, Australia.
Scott
Heather L
HL
Dodd
Peter R
PR
D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D015317:Biogenic Polyamines / Q000502:physiology; D018846:Excitatory Amino Acids / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology*; D006801:Humans; D009410:Nerve Degeneration / Q000503:physiopathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
D015317:Biogenic Polyamines; D018846:Excitatory Amino Acids; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid