Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis

The deposition of aggregated amyloid-β peptides derived from the pro-amyloidogenic processing of the amyloid precurson protein (APP) into characteristic amyloid plaques (APs) is distinctive to Alzheimer’s disease (AD). Alternative APP processing via the metalloprotease ADAM10 prevents amyloid-β form...

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Autores: Esteve, Pilar, Rueda-Carrasco, Javier, Mateo, María I., Martín-Bermejo, María Jesús, Draffin, Jonathan E., Pereyra, Guadalupe, Sandonís, África, Crespo, Inmaculada, Moreno, Inmaculada, Aso, Ester, García-Esparcia, Paula, Gómez-Tortosa, Estrella, Rábano, Alberto, Fortea, Juan, Alcolea, Daniel, Lleó, Alberto, Heneka, Michael T., Valpuesta, José M., Esteban, José A., Ferrer, Isidro, Domínguez, Mercedes, Bovolenta, Paola
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/193936
Acceso en línea:http://hdl.handle.net/10261/193936
Access Level:acceso abierto
Palabra clave:ddc:570
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repository_id_str
spelling Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesisEsteve, PilarRueda-Carrasco, JavierMateo, María I.Martín-Bermejo, María JesúsDraffin, Jonathan E.Pereyra, GuadalupeSandonís, ÁfricaCrespo, InmaculadaMoreno, InmaculadaAso, EsterGarcía-Esparcia, PaulaGómez-Tortosa, EstrellaRábano, AlbertoFortea, JuanAlcolea, DanielLleó, AlbertoHeneka, Michael T.Valpuesta, José M.Esteban, José A.Ferrer, IsidroDomínguez, MercedesBovolenta, Paoladdc:570The deposition of aggregated amyloid-β peptides derived from the pro-amyloidogenic processing of the amyloid precurson protein (APP) into characteristic amyloid plaques (APs) is distinctive to Alzheimer’s disease (AD). Alternative APP processing via the metalloprotease ADAM10 prevents amyloid-β formation. We tested whether downregulation of ADAM10 activity by its secreted endogenous inhibitor secreted-frizzled-related protein 1 (SFRP1) is a common trait of sporadic AD. We demonstrate that SFRP1 is significantly increased in the brain and cerebrospinal fluid of patients with AD, accumulates in APs and binds to amyloid-β, hindering amyloid-β protofibril formation. Sfrp1 overexpression in an AD-like mouse model anticipates the appearance of APs and dystrophic neurites, whereas its genetic inactivation or the infusion of α-SFRP1-neutralizing antibodies favors non-amyloidogenic APP processing. Decreased Sfrp1 function lowers AP accumulation, improves AD-related histopathological traits and prevents long-term potentiation loss and cognitive deficits. Our study unveils SFRP1 as a crucial player in AD pathogenesis and a promising AD therapeutic target.Spanish MINECO (BFU2013-43213-P; BFU2016-75412-R with FEDER support), Fundación Tatiana Perez de Guzman el Bueno and CIBERER to PB and PE, and FIS PI11/3035 to AL. JRC (BES-2011-047189), MIM (BES-2014-068797) and GP (BES-2017-08031 and Fundación Ramon Areces.Peer reviewedMinisterio de Economía y Competitividad (España)Fundación Tatiana Pérez de Guzmán el BuenoFundación Ramón ArecesConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192019info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/193936reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés10.1038/s41593-019-0432-1Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1939362026-05-22T06:33:51Z
dc.title.none.fl_str_mv Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis
title Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis
spellingShingle Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis
Esteve, Pilar
ddc:570
title_short Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis
title_full Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis
title_fullStr Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis
title_full_unstemmed Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis
title_sort Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis
dc.creator.none.fl_str_mv Esteve, Pilar
Rueda-Carrasco, Javier
Mateo, María I.
Martín-Bermejo, María Jesús
Draffin, Jonathan E.
Pereyra, Guadalupe
Sandonís, África
Crespo, Inmaculada
Moreno, Inmaculada
Aso, Ester
García-Esparcia, Paula
Gómez-Tortosa, Estrella
Rábano, Alberto
Fortea, Juan
Alcolea, Daniel
Lleó, Alberto
Heneka, Michael T.
Valpuesta, José M.
Esteban, José A.
Ferrer, Isidro
Domínguez, Mercedes
Bovolenta, Paola
author Esteve, Pilar
author_facet Esteve, Pilar
Rueda-Carrasco, Javier
Mateo, María I.
Martín-Bermejo, María Jesús
Draffin, Jonathan E.
Pereyra, Guadalupe
Sandonís, África
Crespo, Inmaculada
Moreno, Inmaculada
Aso, Ester
García-Esparcia, Paula
Gómez-Tortosa, Estrella
Rábano, Alberto
Fortea, Juan
Alcolea, Daniel
Lleó, Alberto
Heneka, Michael T.
Valpuesta, José M.
Esteban, José A.
Ferrer, Isidro
Domínguez, Mercedes
Bovolenta, Paola
author_role author
author2 Rueda-Carrasco, Javier
Mateo, María I.
Martín-Bermejo, María Jesús
Draffin, Jonathan E.
Pereyra, Guadalupe
Sandonís, África
Crespo, Inmaculada
Moreno, Inmaculada
Aso, Ester
García-Esparcia, Paula
Gómez-Tortosa, Estrella
Rábano, Alberto
Fortea, Juan
Alcolea, Daniel
Lleó, Alberto
Heneka, Michael T.
Valpuesta, José M.
Esteban, José A.
Ferrer, Isidro
Domínguez, Mercedes
Bovolenta, Paola
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Fundación Tatiana Pérez de Guzmán el Bueno
Fundación Ramón Areces
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv ddc:570
topic ddc:570
description The deposition of aggregated amyloid-β peptides derived from the pro-amyloidogenic processing of the amyloid precurson protein (APP) into characteristic amyloid plaques (APs) is distinctive to Alzheimer’s disease (AD). Alternative APP processing via the metalloprotease ADAM10 prevents amyloid-β formation. We tested whether downregulation of ADAM10 activity by its secreted endogenous inhibitor secreted-frizzled-related protein 1 (SFRP1) is a common trait of sporadic AD. We demonstrate that SFRP1 is significantly increased in the brain and cerebrospinal fluid of patients with AD, accumulates in APs and binds to amyloid-β, hindering amyloid-β protofibril formation. Sfrp1 overexpression in an AD-like mouse model anticipates the appearance of APs and dystrophic neurites, whereas its genetic inactivation or the infusion of α-SFRP1-neutralizing antibodies favors non-amyloidogenic APP processing. Decreased Sfrp1 function lowers AP accumulation, improves AD-related histopathological traits and prevents long-term potentiation loss and cognitive deficits. Our study unveils SFRP1 as a crucial player in AD pathogenesis and a promising AD therapeutic target.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/193936
url http://hdl.handle.net/10261/193936
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv 10.1038/s41593-019-0432-1
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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