a-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.

BACKGROUND: The disintegrin metalloproteinase 10 (ADAM10) is the main a-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: C...

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Autores: Agüero P, Sainz MJ, García-Ayllón MS, Sáez-Valero J, Téllez R, Guerrero-López R, Pérez-Pérez J, Jiménez-Escrig A, Gómez-Tortosa E
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Instituto de Investigación Biomédica y Sanitaria de Alicante (ISABIAL)
Repositorio:r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante
OAI Identifier:oai:isabial.fundanetsuite.com:p6835
Acceso en línea:https://isabial.portalinvestigacion.com/publicaciones6835
https://alzres.biomedcentral.com/articles/10.1186/s13195-020-00708-0
Access Level:acceso abierto
Palabra clave:*ADAM10
*Familial Alzheimer’s disease
*Genetics
*a-Secretase
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network_acronym_str ES
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repository_id_str
spelling a-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.Agüero PSainz MJGarcía-Ayllón MSSáez-Valero JTéllez RGuerrero-López RPérez-Pérez JJiménez-Escrig AGómez-Tortosa E*ADAM10*Familial Alzheimer’s disease*Genetics*a-SecretaseBACKGROUND: The disintegrin metalloproteinase 10 (ADAM10) is the main a-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 sAPPa and sAPPß 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 Aß42, 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 sAPPa peptide, both compared to controls, while sAPPß levels remained unchanged. Interestingly, sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPa and sAPPß levels resembled those of controls. Therefore, a decreased sAPPa/sAPPß 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 a-secretase. This report encourages future research on ADAM10 enhancers.BMC2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://isabial.portalinvestigacion.com/publicaciones6835https://alzres.biomedcentral.com/articles/10.1186/s13195-020-00708-0Alzheimers Research & TherapyISSN: 17589193reponame:r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicanteinstname:Instituto de Investigación Biomédica y Sanitaria de Alicante (ISABIAL)Inglésinfo:eu-repo/semantics/openAccessoai:isabial.fundanetsuite.com:p68352026-06-12T10:20:37Z
dc.title.none.fl_str_mv a-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.
title a-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.
spellingShingle a-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.
Agüero P
*ADAM10
*Familial Alzheimer’s disease
*Genetics
*a-Secretase
title_short a-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.
title_full a-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.
title_fullStr a-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.
title_full_unstemmed a-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.
title_sort a-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.
dc.creator.none.fl_str_mv Agüero P
Sainz MJ
García-Ayllón MS
Sáez-Valero J
Téllez R
Guerrero-López R
Pérez-Pérez J
Jiménez-Escrig A
Gómez-Tortosa E
author Agüero P
author_facet Agüero P
Sainz MJ
García-Ayllón MS
Sáez-Valero J
Téllez R
Guerrero-López R
Pérez-Pérez J
Jiménez-Escrig A
Gómez-Tortosa E
author_role author
author2 Sainz MJ
García-Ayllón MS
Sáez-Valero J
Téllez R
Guerrero-López R
Pérez-Pérez J
Jiménez-Escrig A
Gómez-Tortosa E
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv *ADAM10
*Familial Alzheimer’s disease
*Genetics
*a-Secretase
topic *ADAM10
*Familial Alzheimer’s disease
*Genetics
*a-Secretase
description BACKGROUND: The disintegrin metalloproteinase 10 (ADAM10) is the main a-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 sAPPa and sAPPß 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 Aß42, 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 sAPPa peptide, both compared to controls, while sAPPß levels remained unchanged. Interestingly, sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPa and sAPPß levels resembled those of controls. Therefore, a decreased sAPPa/sAPPß 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 a-secretase. This report encourages future research on ADAM10 enhancers.
publishDate 2020
dc.date.none.fl_str_mv 2020
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://isabial.portalinvestigacion.com/publicaciones6835
https://alzres.biomedcentral.com/articles/10.1186/s13195-020-00708-0
url https://isabial.portalinvestigacion.com/publicaciones6835
https://alzres.biomedcentral.com/articles/10.1186/s13195-020-00708-0
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv Alzheimers Research & Therapy
ISSN: 17589193
reponame:r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante
instname:Instituto de Investigación Biomédica y Sanitaria de Alicante (ISABIAL)
instname_str Instituto de Investigación Biomédica y Sanitaria de Alicante (ISABIAL)
reponame_str r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante
collection r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812455

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