title: Maintenance of membrane organization in the aging mouse brain as the determining factor for preventing receptor dysfunction and for improving response to anti-Alzheimer treatments.
abstract: Although a major risk factor for Alzheimer's disease (AD), the "aging" parameter is not systematically considered in preclinical validation of anti-AD drugs. To explore how aging affects neuronal reactivity to anti-AD agents, the ciliary neurotrophic factor (CNTF)-associated pathway was chosen as a model. Comparison of the neuroprotective properties of CNTF in 6- and 18-month old mice revealed that CNTF resistance in the older animals is associated with the exclusion of the CNTF-receptor subunits from rafts and their subsequent dispersion to non-raft cortical membrane domains. This age-dependent membrane remodeling prevented both the formation of active CNTF-receptor complexes and the activation of prosurvival STAT3 and ERK1/2 pathways, demonstrating that age-altered membranes impaired the reactivity of potential therapeutic targets. CNTF-receptor distribution and CNTF signaling responses were improved in older mice receiving dietary docosahexaenoic acid, with CNTF-receptor functionality being similar to those of younger mice, pointing toward dietary intervention as a promising adjuvant strategy to maintain functional neuronal membranes, thus allowing the associated receptors to respond appropriately to anti-AD agents.
authors.affiliation: UR AFPA - INRA USC 340, EA 3998, Équipe Biodisponibilité et Fonctionnalité des Lipides Alimentaires (BFLA), Université de Lorraine, Nancy, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Colin
authors.affiliation: UR AFPA - INRA USC 340, EA 3998, Équipe Biodisponibilité et Fonctionnalité des Lipides Alimentaires (BFLA), Université de Lorraine, Nancy, France.
authors.forename: Mélanie H
authors.initials: MH
authors.lastname: Thomas
authors.affiliation: UR AFPA - INRA USC 340, EA 3998, Équipe Biodisponibilité et Fonctionnalité des Lipides Alimentaires (BFLA), Université de Lorraine, Nancy, France.
authors.forename: Lynn
authors.initials: L
authors.lastname: Gregory-Pauron
authors.affiliation: UR AFPA - INRA USC 340, EA 3998, Équipe Biodisponibilité et Fonctionnalité des Lipides Alimentaires (BFLA), Université de Lorraine, Nancy, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Pinçon
authors.affiliation: UR AFPA - INRA USC 340, EA 3998, Équipe Biodisponibilité et Fonctionnalité des Lipides Alimentaires (BFLA), Université de Lorraine, Nancy, France.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Lanhers
authors.affiliation: UR AFPA - INRA USC 340, EA 3998, Équipe Biodisponibilité et Fonctionnalité des Lipides Alimentaires (BFLA), Université de Lorraine, Nancy, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Corbier
authors.affiliation: UR AFPA - INRA USC 340, EA 3998, Équipe Biodisponibilité et Fonctionnalité des Lipides Alimentaires (BFLA), Université de Lorraine, Nancy, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Claudepierre
authors.affiliation: UR AFPA - INRA USC 340, EA 3998, Équipe Biodisponibilité et Fonctionnalité des Lipides Alimentaires (BFLA), Université de Lorraine, Nancy, France.
authors.forename: Frances T
authors.initials: FT
authors.lastname: Yen
authors.affiliation: UR AFPA - INRA USC 340, EA 3998, Équipe Biodisponibilité et Fonctionnalité des Lipides Alimentaires (BFLA), Université de Lorraine, Nancy, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Oster
authors.affiliation: UR AFPA - INRA USC 340, EA 3998, Équipe Biodisponibilité et Fonctionnalité des Lipides Alimentaires (BFLA), Université de Lorraine, Nancy, France; Laboratoire de Biochimie et Biologie Moléculaire, UF Oncologie - Endocrinologie - Neurobiologie, Hôpital Central, Centre Hospitalier Universitaire, Nancy, France. Electronic address: catherine.malaplate-armand@univ-lorraine.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Malaplate-Armand
mesh_terms: D000375:Aging / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000166:cytology*; D002462:Cell Membrane / Q000502:physiology*; D020934:Ciliary Neurotrophic Factor / Q000502:physiology; D004042:Dietary Fats, Unsaturated; D004281:Docosahexaenoic Acids; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D021962:Membrane Microdomains; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology*; D018697:Nootropic Agents / Q000627:therapeutic use*; D020801:Receptor, Ciliary Neurotrophic Factor / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020934:Ciliary Neurotrophic Factor; D004042:Dietary Fats, Unsaturated; D018697:Nootropic Agents; D020801:Receptor, Ciliary Neurotrophic Factor; D050796:STAT3 Transcription Factor; D004281:Docosahexaenoic Acids
keywords: Brain aging; Ciliary neurotrophic factor; Dietary lipids; Docosahexaenoic acid; Lipid rafts; Neuronal membranes