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dc.contributor.authorCortes-Canteli, Marta 
dc.contributor.authorKruyer, Anna
dc.contributor.authorFernandez-Nueda, Irene 
dc.contributor.authorMarcos-Diaz, Ana 
dc.contributor.authorCeron, Carlos 
dc.contributor.authorRichards, Allison T
dc.contributor.authorJno-Charles, Odella C
dc.contributor.authorRodriguez, Ignacio 
dc.contributor.authorCallejas, Sergio 
dc.contributor.authorNorris, Erin H
dc.contributor.authorSanchez-Gonzalez, Javier 
dc.contributor.authorRuiz-Cabello, Jesus 
dc.contributor.authorIbáñez, Borja 
dc.contributor.authorStrickland, Sidney
dc.contributor.authorFuster, Valentin 
dc.date.accessioned2019-10-31T11:11:16Z
dc.date.available2019-10-31T11:11:16Z
dc.date.issued2019-10
dc.identifier.citationJ Am Coll Cardiol. 2019; 74(15):1910-1923es_ES
dc.identifier.issn0735-1097es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/8542
dc.description.abstractBACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with important vascular and hemostatic alterations that should be taken into account during diagnosis and treatment. OBJECTIVES: This study evaluates whether anticoagulation with dabigatran, a clinically approved oral direct thrombin inhibitor with a low risk of intracerebral hemorrhage, ameliorates AD pathogenesis in a transgenic mouse model of AD. METHODS: TgCRND8 AD mice and their wild-type littermates were treated for 1 year with dabigatran etexilate or placebo. Cognition was evaluated using the Barnes maze, and cerebral perfusion was examined by arterial spin labeling. At the molecular level, Western blot and histochemical analyses were performed to analyze fibrin content, amyloid burden, neuroinflammatory activity, and blood-brain barrier (BBB) integrity. RESULTS: Anticoagulation with dabigatran prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the AD mouse brain. In addition, long-term dabigatran treatment significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and infiltrated T cells by 23.7%, 51.8%, 31.3%, and 32.2%, respectively. Dabigatran anticoagulation also prevented AD-related astrogliosis and pericyte alterations, and maintained expression of the water channel aquaporin-4 at astrocytic perivascular endfeet of the BBB. CONCLUSIONS: Long-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and amyloid deposition in AD mice. Our results open a field for future investigation on whether the use of direct oral anticoagulants might be of therapeutic value in AD.es_ES
dc.description.sponsorshipThis work was funded by a Proof-of-Concept Award from the Robertson Therapeutic Development Fund (Dr. Cortes-Canteli), The Rockefeller University; NINDS/NIH grant NIS106668 (Drs. Norris and Strickland); European Union’s Seventh Framework Programme (FP7-PEOPLE-2013-IIF), grant agreement n PIIF-GA-2013-624811 (Drs. Cortes-Canteli and Fuster), CNIC, Madrid, Spain; Miguel Servet type I research contract (CP16/00174 and MS16/00174 [Dr. Cortes-Canteli]), Instituto de Salud Carlos III (ISCIII), CNIC; Iniciativa de Empleo Juvenil (PEJ16/MED/TL-1231 [A. Marcos-Diaz] and PEJ-2018-AI/BMD-11477 [C. Ceron]) from Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid; European Regional Development Funds (FEDER “Una manera de hacer Europa”) and European Social Funds (FSE “El FSE invierte en tu futuro”); and with the support of the Marie Curie Alumni Association (Dr. Cortes-Canteli). The CNIC is supported by the ISCIII, the Spanish Ministerio de Ciencia, Innovación y Universidades (MCNU), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). CIC biomaGUNE is a Maria de Maeztu Unit of Excellence (MDM-2017-0720). Dr. Sanchez-Gonzalez is an employee of Philips Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.es_ES
dc.language.isoenges_ES
dc.publisherElsevier es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAnimal models of human diseasees_ES
dc.subjectCognitive impairmentes_ES
dc.subjectNeuroinflammationes_ES
dc.subjectOral anticoagulationes_ES
dc.subjectThrombines_ES
dc.subjectThrombosises_ES
dc.titleLong-Term Dabigatran Treatment Delays Alzheimer's Disease Pathogenesis in the TgCRND8 Mouse Modeles_ES
dc.typejournal articlees_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.identifier.pubmedID31601371es_ES
dc.format.volume74es_ES
dc.format.number15es_ES
dc.format.page1910-1923es_ES
dc.identifier.doi10.1016/j.jacc.2019.07.081es_ES
dc.contributor.funderRobertson Therapeutic Development Fund (Estados Unidos)
dc.contributor.funderRockefeller University (Estados Unidos) 
dc.contributor.funderNational Institutes of Health (Estados Unidos) 
dc.contributor.funderUnión Europea. Comisión Europea 
dc.contributor.funderCentro Nacional de Investigaciones Cardiovasculares Carlos III (España) 
dc.contributor.funderComunidad de Madrid (España) 
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderUnión Europea. Fondo Social Europeo (ESF/FSE) 
dc.contributor.funderFundación ProCNIC 
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España) 
dc.description.peerreviewedes_ES
dc.identifier.e-issn1558-3597es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.jacc.2019.07.081es_ES
dc.identifier.journalJournal of the American College of Cardiologyes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Imagen Cardiovascular y Estudios Poblacionaleses_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Laboratorio Traslacional para la Imagen y Terapia Cardiovasculares_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Genómicaes_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/624811es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SEV-2015-0505es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/MDM-2017-0720es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/CP16/00174es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/MS16/00174es_ES
dc.rights.accessRightsopen accesses_ES


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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 Internacional