title: Peripheral Interventions Enhancing Brain Glutamate Homeostasis Relieve Amyloid β- and TNFα- Mediated Synaptic Plasticity Disruption in the Rat Hippocampus.
abstract: Dysregulation of glutamate homeostasis in the interstitial fluid of the brain is strongly implicated in causing synaptic dysfunction in many neurological and psychiatric illnesses. In the case of Alzheimer's disease (AD), amyloid β (Aβ)-mediated disruption of synaptic plasticity and memory can be alleviated by interventions that directly remove glutamate or block certain glutamate receptors. An alternative strategy is to facilitate the removal of excess glutamate from the nervous system by activating peripheral glutamate clearance systems. One such blood-based system, glutamate oxaloacetate transaminase (GOT), is activated by oxaloacetate, which acts as a co-substrate. We report here that synthetic and AD brain-derived Aβ-mediated inhibition of synaptic long-term potentiation in the hippocampus is alleviated by oxaloacetate. Moreover the effect of oxaloacetate was GOT-dependent. The disruptive effects of a general inhibitor of excitatory amino acid transport or TNFα, a pro-inflammatory mediator of Aβ action, were also reversed by oxaloacetate. Furthermore, another intervention that increases peripheral glutamate clearance, peritoneal dialysis, mimicked the beneficial effect of oxaloacetate. These findings lend support to the promotion of the peripheral clearance of glutamate as a means to alleviate synaptic dysfunction that is caused by impaired glutamate homeostasis in the brain.
authors.affiliation: Department of Pharmacology and Therapeutics, and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Dainan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Mably
authors.affiliation: Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.affiliation: Department of Pharmacology and Therapeutics, and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000494:pharmacology; D001224:Aspartic Acid / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D018698:Glutamic Acid / Q000097:blood*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D062907:Oxaloacetic Acid / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); C120673:benzyloxyaspartate; D062907:Oxaloacetic Acid; D001224:Aspartic Acid; D018698:Glutamic Acid; D024443:Aspartate Aminotransferase, Cytoplasmic
keywords: Alzheimer's disease; TNFα; amyloid beta; glutamate clearance; long-term potentiation