title: Secreted form of amyloid precursor protein enhances basal glucose and glutamate transport and protects against oxidative impairment of glucose and glutamate transport in synaptosomes by a cyclic GMP-mediated mechanism.
abstract: Synaptic dysfunction and degeneration are believed to underlie the cognitive deficits that characterize Alzheimer's disease, and overactivation of glutamate receptors under conditions of increased oxidative stress and metabolic compromise may contribute to the neurodegenerative process in many different disorders. The secreted form of amyloid precursor protein (sAPPalpha), which is released from neurons in an activity-dependent manner, can modulate neurite outgrowth, synaptic plasticity, and neuron survival. We now report that sAPPalpha can enhance glucose and glutamate transport in synaptic compartments. Treatment of cortical synaptosomes with nanomolar concentrations of sAPPalpha resulted in an attenuation of impairment of glutamate and glucose transport induced by exposure to amyloid beta-peptide and Fe2+. The protective effect of sAPPalpha was mimicked by treatment with 8-bromo-cyclic GMP and blocked by a cyclic GMP-dependent protein kinase inhibitor, suggesting that protective action of sAPPalpha is mediated by cyclic GMP. Our data suggest that glucose and glutamate transport can be regulated locally at the level of the synapse and further suggest important roles for sAPPalpha and cyclic GMP in modulating synaptic physiology under normal and pathophysiological conditions.
authors.affiliation: Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Z H
authors.initials: ZH
authors.lastname: Guo
authors.forename: J D
authors.initials: JD
authors.lastname: Geiger
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001692:Biological Transport / Q000502:physiology; D002227:Carbazoles; D002540:Cerebral Cortex / Q000166:cytology; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005296:Ferrous Compounds / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D007211:Indoles; D015227:Lipid Peroxidation / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism*; D014316:Tritium
chemical_list: D000470:Alkaloids; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005296:Ferrous Compounds; D007211:Indoles; D009498:Neurotoxins; D014316:Tritium; C073601:KT 5823; D015124:8-Bromo Cyclic Adenosine Monophosphate; C020748:ferrous sulfate; D018698:Glutamic Acid; D006152:Cyclic GMP; D005947:Glucose