The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease

[EN] Reelin is a signaling protein that plays a crucial role in synaptic function, which expression is influenced by β-amyloid (Aβ). We show that Reelin and Aβ oligomers co-immunoprecipitated in human brain extracts and were present in the same size-exclusion chromatography fractions. Aβ treatment o...

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Authors: Cuchillo Ibáñez, Inmaculada, Mata Balaguer, Trinidad, Balmaceda, Valeria, Arranz Santos, Juan José, Nimpf, Johannes, Sáez Valero, Javier
Format: article
Status:Published version
Publication Date:2016
Country:España
Institution:Universidad de León
Repository:BULERIA. Repositorio Institucional de la Universidad de León
OAI Identifier:oai:buleria.unileon.es:10612/24344
Online Access:https://www.nature.com/articles/srep31646
https://hdl.handle.net/10612/24344
Access Level:Open access
Keyword:Biología
Genética
B-amyloid
Reelin
Alzheimer´s disease
2409 Genética
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spelling The β-amyloid peptide compromises Reelin signaling in Alzheimer’s diseaseCuchillo Ibáñez, InmaculadaMata Balaguer, TrinidadBalmaceda, ValeriaArranz Santos, Juan JoséNimpf, JohannesSáez Valero, JavierBiologíaGenéticaB-amyloidReelinAlzheimer´s disease2409 Genética[EN] Reelin is a signaling protein that plays a crucial role in synaptic function, which expression is influenced by β-amyloid (Aβ). We show that Reelin and Aβ oligomers co-immunoprecipitated in human brain extracts and were present in the same size-exclusion chromatography fractions. Aβ treatment of cells led to increase expression of Reelin, but secreted Reelin results trapped together with Aβ aggregates. In frontal cortex extracts an increase in Reelin mRNA, and in soluble and insoluble (guanidine-extractable) Reelin protein, was associated with late Braak stages of Alzheimer's disease (AD), while expression of its receptor, ApoER2, did not change. However, Reelin-dependent induction of Dab1 phosphorylation appeared reduced in AD. In cells, Aβ reduced the capacity of Reelin to induce internalization of biotinylated ApoER2 and ApoER2 processing. Soluble proteolytic fragments of ApoER2 generated after Reelin binding can be detected in cerebrospinal fluid (CSF). Quantification of these soluble fragments in CSF could be a tool to evaluate the efficiency of Reelin signaling in the brain. These CSF-ApoER2 fragments correlated with Reelin levels only in control subjects, not in AD, where these fragments diminished. We conclude that while Reelin expression is enhanced in the Alzheimer's brain, the interaction of Reelin with Aβ hinders its biological activitySIWe thank Prof. T. Curran (Eppley Institute, University of Nebraska Medical Center, Omaha, USA) for generously providing cDNAs, and Drs M. Calero (CIBERNED, Spain) and José-Manuel Mingot (Inst. Neurociencias, Universidad Miguel Hernández-CSIC, Spain) for technical advice. This work was supported by grants from the Fundación Ramón Areces, Fondo de Investigaciones Sanitarias (PI11/03026; PI12/00593; PI15/00665 cofunded by the Fondo Europeo de Desarrollo Regional), and under the aegis of the EU BIOMARKAPD-Joint Programming on Neurodegenerative Diseases (JPND) project; and through CIBERNED (Instituto de Salud Carlos III, Spain). VB was supported by a JAE-Predoctoral fellowship from the CSIC (Spain), co-funded by the Fondo Social Europeo (FSE), E.C.Nature ResearchProducción AnimalFacultad de Veterinaria2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://www.nature.com/articles/srep31646https://hdl.handle.net/10612/24344reponame:BULERIA. Repositorio Institucional de la Universidad de Leóninstname:Universidad de LeónInglésinfo:eu-repo/grantAgreement/MICINN/Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia/PI11info:eu-repo/grantAgreement/MINECO/Acción Estratégica de Salud/ PI12info:eu-repo/grantAgreement/MINECO/Programa Estatal de I+D+I Orientada a los Retos de la Sociedad/ PI15http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:buleria.unileon.es:10612/243442026-06-24T12:43:27Z
dc.title.none.fl_str_mv The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease
title The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease
spellingShingle The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease
Cuchillo Ibáñez, Inmaculada
Biología
Genética
B-amyloid
Reelin
Alzheimer´s disease
2409 Genética
title_short The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease
title_full The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease
title_fullStr The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease
title_full_unstemmed The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease
title_sort The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease
dc.creator.none.fl_str_mv Cuchillo Ibáñez, Inmaculada
Mata Balaguer, Trinidad
Balmaceda, Valeria
Arranz Santos, Juan José
Nimpf, Johannes
Sáez Valero, Javier
author Cuchillo Ibáñez, Inmaculada
author_facet Cuchillo Ibáñez, Inmaculada
Mata Balaguer, Trinidad
Balmaceda, Valeria
Arranz Santos, Juan José
Nimpf, Johannes
Sáez Valero, Javier
author_role author
author2 Mata Balaguer, Trinidad
Balmaceda, Valeria
Arranz Santos, Juan José
Nimpf, Johannes
Sáez Valero, Javier
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Producción Animal
Facultad de Veterinaria
dc.subject.none.fl_str_mv Biología
Genética
B-amyloid
Reelin
Alzheimer´s disease
2409 Genética
topic Biología
Genética
B-amyloid
Reelin
Alzheimer´s disease
2409 Genética
description [EN] Reelin is a signaling protein that plays a crucial role in synaptic function, which expression is influenced by β-amyloid (Aβ). We show that Reelin and Aβ oligomers co-immunoprecipitated in human brain extracts and were present in the same size-exclusion chromatography fractions. Aβ treatment of cells led to increase expression of Reelin, but secreted Reelin results trapped together with Aβ aggregates. In frontal cortex extracts an increase in Reelin mRNA, and in soluble and insoluble (guanidine-extractable) Reelin protein, was associated with late Braak stages of Alzheimer's disease (AD), while expression of its receptor, ApoER2, did not change. However, Reelin-dependent induction of Dab1 phosphorylation appeared reduced in AD. In cells, Aβ reduced the capacity of Reelin to induce internalization of biotinylated ApoER2 and ApoER2 processing. Soluble proteolytic fragments of ApoER2 generated after Reelin binding can be detected in cerebrospinal fluid (CSF). Quantification of these soluble fragments in CSF could be a tool to evaluate the efficiency of Reelin signaling in the brain. These CSF-ApoER2 fragments correlated with Reelin levels only in control subjects, not in AD, where these fragments diminished. We conclude that while Reelin expression is enhanced in the Alzheimer's brain, the interaction of Reelin with Aβ hinders its biological activity
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://www.nature.com/articles/srep31646
https://hdl.handle.net/10612/24344
url https://www.nature.com/articles/srep31646
https://hdl.handle.net/10612/24344
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MICINN/Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia/PI11
info:eu-repo/grantAgreement/MINECO/Acción Estratégica de Salud/ PI12
info:eu-repo/grantAgreement/MINECO/Programa Estatal de I+D+I Orientada a los Retos de la Sociedad/ PI15
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv reponame:BULERIA. Repositorio Institucional de la Universidad de León
instname:Universidad de León
instname_str Universidad de León
reponame_str BULERIA. Repositorio Institucional de la Universidad de León
collection BULERIA. Repositorio Institucional de la Universidad de León
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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