title: Peripherally triggered and GSK-3β-driven brain inflammation differentially skew adult hippocampal neurogenesis, behavioral pattern separation and microglial activation in response to ibuprofen.
abstract: Both familial and sporadic forms of Alzheimer disease (AD) present memory impairments. It has been proposed that these impairments are related to inflammation in relevant brain areas such as the hippocampus. Whether peripherally triggered and neuron-driven brain inflammation produce similar and equally reversible alterations is a matter of discussion. Here we studied the effects of ibuprofen administration on a familial AD mouse model overexpressing GSK-3β that presents severe brain inflammation. We compared these effects with those observed in a peripherally triggered brain inflammation model based on chronic lipopolysaccharide (LPS) administration. Both proinflammatory stimuli produced equivalent reversible morphological alterations in granule neurons; however, GSK-3β had a much more prominent role in newborn neuron connectivity, causing alterations that were not reversed by ibuprofen. Although both insults triggered similar behavioral impairments, ibuprofen rescued this defect in LPS-treated mice but did not produce any improvement in GSK-3β-overexpressing animals. This observation could be attributable to the different microglial phenotype induced by ibuprofen treatment. These data may be clinically relevant for AD therapies, as GSK-3β appears to determine the efficacy of ibuprofen treatment.
authors.affiliation: 1] Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Llorens-Martín
authors.affiliation: 1] Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Jurado-Arjona
authors.affiliation: 1] Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Fuster-Matanzo
authors.affiliation: 1] Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Hernández
authors.affiliation: 1] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain [2] Neuropathology Department, CIEN Foundation, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rábano
authors.affiliation: 1] Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Ávila
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D007052:Ibuprofen / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D007052:Ibuprofen