α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease

[Background]: The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of APP. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset AD, though clear clinical-genetic correlates remain elusive.

Detalhes bibliográficos
Autores: Agüero, Pablo, Sainz, María José, García-Ayllón, María-Salud, Sáez-Valero, Javier, Téllez, Raquel, Guerrero-López, Rosa, Pérez-Pérez, Julián, Jiménez-Escrig, Adriano, Gómez-Tortosa, Estrella
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2020
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositório:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/231210
Acesso em linha:http://hdl.handle.net/10261/231210
Access Level:Acceso aberto
id ES_06446a1be64609803a67fa85bc29cc65
oai_identifier_str oai:digital.csic.es:10261/231210
network_acronym_str ES
network_name_str España
repository_id_str
spelling α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s diseaseAgüero, PabloSainz, María JoséGarcía-Ayllón, María-SaludSáez-Valero, JavierTéllez, RaquelGuerrero-López, RosaPérez-Pérez, JuliánJiménez-Escrig, AdrianoGómez-Tortosa, Estrella[Background]: The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of APP. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset AD, though clear clinical-genetic correlates remain elusive.[Methods]: Clinical-genetic and biomarker study of a first family with early- and late-onset AD associated with a nonsense ADAM10 mutation (p.Tyr167*). CSF analysis included AD core biomarkers, as well as Western blot of ADAM10 species and sAPPα and sAPPβ peptides. We evaluate variant’s pathogenicity, pattern of segregation, and further screened for the p.Tyr167* mutation in 197 familial AD cases from the same cohort, 200 controls from the same background, and 274 AD cases from an independent Spanish cohort.[Results]: The mutation was absent from public databases and segregated with the disease. CSF Aβ42, total tau, and phosphorylated tau of affected siblings were consistent with AD. The predicted haploinsufficiency effect of the nonsense mutation was supported by (a) ADAM10 isoforms in CSF decreased around 50% and (b) 70% reduction of CSF sAPPα peptide, both compared to controls, while sAPPβ levels remained unchanged. Interestingly, sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPα and sAPPβ levels resembled those of controls. Therefore, a decreased sAPPα/sAPPβ ratio was an exclusive feature of mutant ADAM10 siblings. The p.Tyr167* mutation was not found in any of the other AD cases or controls screened.[Conclusions]: This family illustrates the role of ADAM10 in the amyloidogenic process and the clinical development of the disease. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model for sporadic late-onset AD due to age-related downregulation of α-secretase. This report encourages future research on ADAM10 enhancers.This work was supported by grants from the Ministry of Sciences and Technology, (SAF2010-18277), Instituto de Salud Carlos III (FIS14/00099), Direcció General d’Universitat, Investigació i Ciència, GVA (AICO/2018/090), and FEDER funds, Spain. MSGA is supported by a Miguel Servet II Grant from Instituto de Salud Carlos III (CPII16/00011).Peer reviewedBioMed CentralMinisterio de Economía y Competitividad (España)Generalitat ValencianaInstituto de Salud Carlos IIIEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202120212020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/231210reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1186/s13195-020-00708-0Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2312102026-05-22T06:33:51Z
dc.title.none.fl_str_mv α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease
title α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease
spellingShingle α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease
Agüero, Pablo
title_short α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease
title_full α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease
title_fullStr α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease
title_full_unstemmed α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease
title_sort α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease
dc.creator.none.fl_str_mv Agüero, Pablo
Sainz, María José
García-Ayllón, María-Salud
Sáez-Valero, Javier
Téllez, Raquel
Guerrero-López, Rosa
Pérez-Pérez, Julián
Jiménez-Escrig, Adriano
Gómez-Tortosa, Estrella
author Agüero, Pablo
author_facet Agüero, Pablo
Sainz, María José
García-Ayllón, María-Salud
Sáez-Valero, Javier
Téllez, Raquel
Guerrero-López, Rosa
Pérez-Pérez, Julián
Jiménez-Escrig, Adriano
Gómez-Tortosa, Estrella
author_role author
author2 Sainz, María José
García-Ayllón, María-Salud
Sáez-Valero, Javier
Téllez, Raquel
Guerrero-López, Rosa
Pérez-Pérez, Julián
Jiménez-Escrig, Adriano
Gómez-Tortosa, Estrella
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Generalitat Valenciana
Instituto de Salud Carlos III
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description [Background]: The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of APP. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset AD, though clear clinical-genetic correlates remain elusive.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/231210
url http://hdl.handle.net/10261/231210
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1186/s13195-020-00708-0
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
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
_version_ 1869402905639911424
score 15,812455

Registros relacionados