APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the main cause of dementia in the elderly. The disease has a high impact on individuals and their families and represents a growing public health and socio-economic burden. Despite this, there is no effective treatment opt...

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Autores: Lapresa, Rebeca, Agulla, Jesús, Bolaños, Juan P., Almeida, Angeles
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/296006
Acceso en línea:http://hdl.handle.net/10261/296006
Access Level:acceso abierto
Palabra clave:Cdh1
Neurodegeneration
Alzheimer’s disease
Molecular targets
Therapy
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spelling APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s diseaseLapresa, RebecaAgulla, JesúsBolaños, Juan P.Almeida, AngelesCdh1NeurodegenerationAlzheimer’s diseaseMolecular targetsTherapyAlzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the main cause of dementia in the elderly. The disease has a high impact on individuals and their families and represents a growing public health and socio-economic burden. Despite this, there is no effective treatment options to cure or modify the disease progression, highlighting the need to identify new therapeutic targets. Synapse dysfunction and loss are early pathological features of Alzheimer’s disease, correlate with cognitive decline and proceed with neuronal death. In the last years, the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C) has emerged as a key regulator of synaptic plasticity and neuronal survival. To this end, the ligase binds Cdh1, its main activator in the brain. However, inactivation of the anaphase promoting complex/cyclosome-Cdh1 complex triggers dendrite disruption, synapse loss and neurodegeneration, leading to memory and learning impairment. Interestingly, oligomerized amyloid-β (Aβ) peptide, which is involved in Alzheimer’s disease onset and progression, induces Cdh1 phosphorylation leading to anaphase promoting complex/cyclosome-Cdh1 complex disassembly and inactivation. This causes the aberrant accumulation of several anaphase promoting complex/cyclosome-Cdh1 targets in the damaged areas of Alzheimer’s disease brains, including Rock2 and Cyclin B1. Here we review the function of anaphase promoting complex/cyclosome-Cdh1 dysregulation in the pathogenesis of Alzheimer’s disease, paying particular attention in the neurotoxicity induced by its molecular targets. Understanding the role of anaphase promoting complex/cyclosome-Cdh1-targeted substrates in Alzheimer’s disease may be useful in the development of new effective disease-modifying treatments for this neurological disorder.AA is funded by The Instituto de Salud Carlos III (PI21/00727, co-funded by the European Union). JB is funded by Agencia Estatal de Investigación (PID2019-105699RBI00). The Institute of Functional Biology and Genomics is funded by the Junta de Castilla y León (CLU-2017-03 co-funded by the P.O. FEDER CyL 14-20; CL-EI-2021-08, co-funded by the European Union ERDF). RL and JA are funded by Junta de Castilla y León (CSI151P20).Frontiers MediaInstituto de Salud Carlos IIIEuropean CommissionAgencia Estatal de Investigación (España)Junta de Castilla y LeónConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2023202320222023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/296006reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI21%2F00727info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105699RB-I00https://doi.org/10.3389/fphar.2022.1086540Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2960062026-05-22T06:33:51Z
dc.title.none.fl_str_mv APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s disease
title APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s disease
spellingShingle APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s disease
Lapresa, Rebeca
Cdh1
Neurodegeneration
Alzheimer’s disease
Molecular targets
Therapy
title_short APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s disease
title_full APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s disease
title_fullStr APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s disease
title_full_unstemmed APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s disease
title_sort APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s disease
dc.creator.none.fl_str_mv Lapresa, Rebeca
Agulla, Jesús
Bolaños, Juan P.
Almeida, Angeles
author Lapresa, Rebeca
author_facet Lapresa, Rebeca
Agulla, Jesús
Bolaños, Juan P.
Almeida, Angeles
author_role author
author2 Agulla, Jesús
Bolaños, Juan P.
Almeida, Angeles
author2_role author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Agencia Estatal de Investigación (España)
Junta de Castilla y León
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cdh1
Neurodegeneration
Alzheimer’s disease
Molecular targets
Therapy
topic Cdh1
Neurodegeneration
Alzheimer’s disease
Molecular targets
Therapy
description Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the main cause of dementia in the elderly. The disease has a high impact on individuals and their families and represents a growing public health and socio-economic burden. Despite this, there is no effective treatment options to cure or modify the disease progression, highlighting the need to identify new therapeutic targets. Synapse dysfunction and loss are early pathological features of Alzheimer’s disease, correlate with cognitive decline and proceed with neuronal death. In the last years, the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C) has emerged as a key regulator of synaptic plasticity and neuronal survival. To this end, the ligase binds Cdh1, its main activator in the brain. However, inactivation of the anaphase promoting complex/cyclosome-Cdh1 complex triggers dendrite disruption, synapse loss and neurodegeneration, leading to memory and learning impairment. Interestingly, oligomerized amyloid-β (Aβ) peptide, which is involved in Alzheimer’s disease onset and progression, induces Cdh1 phosphorylation leading to anaphase promoting complex/cyclosome-Cdh1 complex disassembly and inactivation. This causes the aberrant accumulation of several anaphase promoting complex/cyclosome-Cdh1 targets in the damaged areas of Alzheimer’s disease brains, including Rock2 and Cyclin B1. Here we review the function of anaphase promoting complex/cyclosome-Cdh1 dysregulation in the pathogenesis of Alzheimer’s disease, paying particular attention in the neurotoxicity induced by its molecular targets. Understanding the role of anaphase promoting complex/cyclosome-Cdh1-targeted substrates in Alzheimer’s disease may be useful in the development of new effective disease-modifying treatments for this neurological disorder.
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
2023
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/10261/296006
url http://hdl.handle.net/10261/296006
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI21%2F00727
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105699RB-I00
https://doi.org/10.3389/fphar.2022.1086540
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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
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