title: Age-dependent changes in the glutamate-nitric oxide pathway in the hippocampus of the triple transgenic model of Alzheimer's disease: implications for neurometabolic regulation.
abstract: Age-dependent changes in nitric oxide ((•)NO) concentration dynamics may play a significant role in both decaying synaptic and metabolic functions in Alzheimer's disease (AD). This neuromodulator acts presynaptically to increase vesicle release and glutamatergic transmission and also regulates mitochondrial function. Under conditions of altered intracellular redox environment, (•)NO may react and produce reactive species such as peroxynitrite. Using the triple transgenic mouse model of AD (3xTgAD), we investigated age-dependent changes in the glutamate-(•)NO axis in the hippocampus. Direct measurement of (•)NO concentration dynamics revealed a significant increase in N-methyl-D-aspartate type receptor-evoked peak (•)NO in the 3xTgAD model at an early age. Aging produced a decrease in peak (•)NO accompanied by significant decrease in production and decay rates in the transgenic model. Evaluation of energy metabolism revealed age-dependent decrease in basal oxygen consumption rate, a general decrease in mitochondrial oxidative phosphorylation parameters, and loss in mitochondrial sparing capacity in both genotypes. Finally, we observed age-dependent increase in 3-nitrotyrosine residues in the hippocampus, consistent with a putative shift in (•)NO bioactivity toward oxidative chemistry associated with neurotoxicity.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Cândida
authors.initials: C
authors.lastname: Dias
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Portugal.
authors.forename: Cátia F
authors.initials: CF
authors.lastname: Lourenço
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Portugal.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Ferreiro
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
authors.forename: Rui M
authors.initials: RM
authors.lastname: Barbosa
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Laranjinha
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. Electronic address: analedo@cnc.uc.pt.
authors.forename: Ana
authors.initials: A
authors.lastname: Ledo
mesh_terms: D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D004734:Energy Metabolism; D018698:Glutamic Acid / Q000378:metabolism* / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism*; D008822:Mice, Transgenic; D008839:Microelectrodes; D008928:Mitochondria / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D030421:Peroxynitrous Acid / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D009435:Synaptic Transmission; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D018698:Glutamic Acid; D014443:Tyrosine
keywords: Alzheimer's disease; Glutamate; High-resolution respirometry; Hippocampus; Microelectrode; Nitric oxide