Hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function
| Autor: | Juan P. Bolaños, Monica Carabias-Carrasco, Angeles Almeida, Silvia Gonzalez-Fernandez, Monica Resch, Joaquim Ros, Seila Fernandez-Fernandez, Raquel Requejo-Aguilar, Veronica Bobo-Jimenez |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), European Commission, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), Junta de Castilla y León, Fundación Ramón Areces, Almeida, Angeles [0000-0003-0485-8904], Almeida, Angeles |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine CK2a calmodulin kinase 2A Clinical Biochemistry Hippocampus CA3 Cornu Ammonis area 3 In vivo knockdown Hippocampal formation Biochemistry DG dendate gyrus chemistry.chemical_compound Cognition PCR polymerase chain reaction 0302 clinical medicine CA1 Cornu Ammonis area 1 shRNA small hairpin RNA Cognitive decline lcsh:QH301-705.5 Neurons lcsh:R5-920 shGCLSFL switched flox shGCL MEFs mouse embryonic fibroblasts GlutathioneIn vivo knockdown GSSG glutathione oxidized form TUJ1 neuron-specific Class III β-tubulin Memory impairment Glutathione medicine.anatomical_structure shGCL shRNA against GCL GSH glutathione reduced form lcsh:Medicine (General) Oxidation-Reduction Research Paper DMSO dimethylsulfoxide SDS sodium dodecyl sulfate MAP2 microtubule-associated protein-2 Dendrite shGCLUFL unswitched flox shGCL Biology Glutamate-cysteine ligase 03 medical and health sciences ROS reactive oxygen species FBS fetal bovine serum In vivo medicine Animals DTNB 5 5′-dithio-bis-(2-nitrobenzoic acid) Redox stress DMEM Dulbecco's modified Eagle's médium TM 4-hydroxy-tamoxifen Organic Chemistry Dendrites Mice Inbred C57BL GCL glutamate-cysteine ligase catalytic subunit Oxidative Stress 030104 developmental biology chemistry nervous system lcsh:Biology (General) Dendrite disruption Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Repositorio Abierto de la UdL Universitad de Lleida Redox Biology, Vol 19, Iss, Pp 52-61 (2018) Digital.CSIC. Repositorio Institucional del CSIC instname Recercat. Dipósit de la Recerca de Catalunya Redox Biology |
| Popis: | Loss of brain glutathione has been associated with cognitive decline and neuronal death during aging and neurodegenerative diseases. However, whether decreased glutathione precedes or follows neuronal dysfunction has not been unambiguously elucidated. Previous attempts to address this issue were approached by fully eliminating glutathione, a strategy causing abrupt lethality or premature neuronal death that led to multiple interpretations. To overcome this drawback, here we aimed to moderately decrease glutathione content by genetically knocking down the rate-limiting enzyme of glutathione biosynthesis in mouse neurons in vivo. Biochemical and morphological analyses of the brain revealed a modest glutathione decrease and redox stress throughout the hippocampus, although neuronal dendrite disruption and glial activation was confined to the hippocampal CA1 layer. Furthermore, the behavioral characterization exhibited signs consistent with cognitive impairment. These results indicate that the hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function. Graphical abstract fx1 Highlights • Whether glutathione fall precedes or follows neuronal dysfunction is unknown. • A genetic approach to downregulate glutathione in neurons in vivo was generated. • Systematic characterization reveals redox stress throughout the hippocampus. • Neuronal dendrite disruption was confined to neurons of the CA1 layer. • Behavioral characterization exhibits cognitive impairment. |
| Databáze: | OpenAIRE |
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