Glutamate-glutamine cycling in Alzheimer's disease.
In addition to its definitive pathological characteristics, neuritic plaques and neurofibrillary tangles, Alzheimer's disease (AD) brain exhibits regionally variable neuronal loss and synaptic dysfunction that are likely to underlie the symptomatic memory loss and language abnormalities. A number of mechanisms that could give rise to this localized damage have been proposed, amongst which excitotoxicity figures prominently. This is the process, well attested in experimental systems, whereby brain cells are excited to death by the pathophysiological action of the brain's most-abundant excitatory transmitter, glutamate. Glutamate transmission is mediated by a range of ionotropic and metabotropic receptors which, when activated, can lead to depolarization and increased intracellular Ca2+ ion concentration in the cells on which they are located. The action of glutamate is terminated by its removal from these receptor sites by transport into nearby cells, most commonly perisynaptic astrocytes. There it is converted to physiologically inert glutamine and shuttled back to excitatory nerve terminals. Malfunctions in components of the glutamate-glutamine cycle could result in a self-perpetuating neuronal death cascade mediated by glutamate. The approval by the FDA of an ionotropic glutamate receptor antagonist to treat late-stage AD has led to renewed interest in the contribution of altered glutamatergic neurotransmission to disease pathogenesis. This review encompasses those aspects of glutamate-glutamine cycling that are altered in AD.
Walton
Heather Scott
HS
School of Molecular and Microbial Science, University of Queensland, Australia. s4067966@student.uq.edu.au
Dodd
Peter R
PR
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D002462:Cell Membrane / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008959:Models, Neurological; D018091:Receptors, AMPA / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology; D018092:Kainic Acid Receptors / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
D018698:Glutamic Acid; D005973:Glutamine; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate