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dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorFernández de Retana, Sofía
dc.contributor.authorMarazuela Fuentes, Paula
dc.contributor.authorSolé Piñol, Montserrat
dc.contributor.authorColell Dinares, Guillem
dc.contributor.authorBonaterra Pastra, Anna
dc.contributor.authorSánchez-Quesada, Jose Luis
dc.contributor.authorMontaner Villalonga, Joan
dc.contributor.authorHernandez Guillamon, Maria Mar
dc.date.accessioned2019-07-05T07:02:39Z
dc.date.available2019-07-05T07:02:39Z
dc.date.issued2019-05-10
dc.identifier.citationFernández de Retana S, Marazuela P, Solé M, Colell G, Bonaterra A, Sánchez-Quesada JL, et al. Peripheral administration of human recombinant ApoJ/clusterin modulates brain beta-amyloid levels in APP23 mice. Alzheimers Res Ther. 2019;11(1):42.
dc.identifier.issn1758-9193
dc.identifier.urihttp://hdl.handle.net/11351/4181
dc.descriptionAPP23; Alzheimer’s disease; ApoJ
dc.description.abstractBACKGROUND: ApoJ/clusterin is a multifunctional protein highly expressed in the brain. The implication of ApoJ in β-amyloid (Aβ) fibrillization and clearance in the context of Alzheimer's disease has been widely studied, although the source and concentration of ApoJ that promotes or inhibits Aβ cerebral accumulation is not clear yet. ApoJ is abundant in plasma and approximately 20% can appear bound to HDL-particles. In this regard, the impact of plasmatic ApoJ and its lipidation status on cerebral β-amyloidosis is still not known. Hence, our main objective was to study the effect of a peripheral increase of free ApoJ or reconstituted HDL particles containing ApoJ in an experimental model of cerebral β-amyloidosis. METHODS: Fourteen-month-old APP23 transgenic mice were subjected to subchronic intravenous treatment with rHDL-rApoJ nanodiscs or free rApoJ for 1 month. Aβ concentration and distribution in the brain, as well as Aβ levels in plasma and CSF, were determined after treatments. Other features associated to AD pathology, such as neuronal loss and neuroinflammation, were also evaluated. RESULTS: Both ApoJ-based treatments prevented the Aβ accumulation in cerebral arteries and induced a decrease in total brain insoluble Aβ42 levels. The peripheral treatment with rApoJ also induced an increase in the Aβ40 levels in CSF, whereas the concentration remained unaltered in plasma. At all the endpoints studied, the lipidation of rApoJ did not enhance the protective properties of free rApoJ. The effects obtained after subchronic treatment with free rApoJ were accompanied by a reduction in hippocampal neuronal loss and an enhancement of the expression of a phagocytic marker in microglial cells surrounding Aβ deposits. Finally, despite the activation of this phagocytic phenotype, treatments did not induce a global neuroinflammatory status. In fact, free rApoJ treatment was able to reduce the levels of interleukin-17 (IL17) and keratinocyte chemoattractant (KC) chemokine in the brain. CONCLUSIONS: Our results demonstrate that an increase in circulating human rApoJ induces a reduction of insoluble Aβ and CAA load in the brain of APP23 mice. Thus, our study suggests that peripheral interventions, based on treatments with multifunctional physiological chaperones, offer therapeutic opportunities to regulate the cerebral Aβ load.
dc.language.isoeng
dc.publisherBMC
dc.relation.ispartofseriesAlzheimer's Research and Therapy;11(1)
dc.rightsAttribution-ShareAlike 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-sa/4.0/
dc.sourceScientia
dc.subjectAlzheimer, Malaltia d' - Tractament
dc.subjectGlicoproteïnes
dc.subjectRatolins transgènics
dc.subject.meshAlzheimer Disease
dc.subject.mesh/drug therapy
dc.subject.meshClusterin
dc.subject.meshMice, Transgenic
dc.titlePeripheral administration of human recombinant ApoJ/clusterin modulates brain beta-amyloid levels in APP23 mice
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1186/s13195-019-0498-8
dc.subject.decsenfermedad de Alzheimer
dc.subject.decs/tratamiento farmacológico
dc.subject.decsclusterina
dc.subject.decsratones transgénicos
dc.relation.publishversionhttps://alzres.biomedcentral.com/articles/10.1186/s13195-019-0498-8
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.organismesInstitut Català de la Salut
dc.contributor.authoraffiliation[Fernández de Retana S, Marazuela P, Solé M, Colell G, Bonaterra A, Montaner J, Hernández-Guillamon M] Laboratori de Recerca Neurovascular, Vall d’Hebron Institut de Recerca, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [Sánchez-Quesada JL] Grup de Bioquímica Cardiovascular, Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona , Spain.
dc.identifier.pmid31077261
dc.identifier.wosWOS:000467681600002
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


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