title: Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation.
abstract: Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by motor and cognitive impairments, involving striatum, cortex and hippocampus. Synaptic and memory dysfunction in HD mouse models have been related to low levels of brain-derived neurotrophic factor (BDNF) and imbalance between TrkB and p75(NTR) receptors. In addition, astrocyte over-activation has also been suggested to contribute to HD cognitive deficits. Fingolimod (FTY720), a modulator of sphingosine-1 phosphate (S1P) receptors, has been shown to increase BDNF levels and to reduce astrogliosis, proving its potential to regulate trophic support and inflammatory response. In this view, we have investigated whether FTY720 improves synaptic plasticity and memory in the R6/1 mouse model of HD, through regulation of BDNF signaling and astroglial reactivity. Chronic administration of FTY720 from pre-symptomatic stages ameliorated long-term memory deficits and dendritic spine loss in CA1 hippocampal neurons from R6/1 mice. Furthermore, FTY720 delivery prevented astrogliosis and over-activation of nuclear factor kappa beta (NF-κB) signaling in the R6/1 hippocampus, reducing tumor necrosis factor alpha (TNFα) and induced nitric oxide synthase (iNOS) levels. TNFα decrease correlated with the normalization of p75(NTR) expression in the hippocampus of FTY720-treated R6/1 mice, thus preventing p75(NTR)/TrkB imbalance. In addition, FTY720 increased cAMP levels and promoted phosphorylation of CREB and RhoA in the hippocampus of R6/1 mice, further supporting its role in the enhancement of synaptic plasticity. Our findings provide new insights into the mechanism of action of FTY720 and reveal a novel therapeutic strategy to treat memory deficits in HD.
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Miguez
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Gerardo
authors.initials: G
authors.lastname: García-Díaz Barriga
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Brito
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Marco
authors.initials: M
authors.lastname: Straccia
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ginés
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Canals
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain alberch@ub.edu.
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008568:Memory / Q000187:drug effects*; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor; D015854:Up-Regulation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D000242:Cyclic AMP; D020813:Receptor, trkB; D000068876:Fingolimod Hydrochloride