Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species

Cytoplasmic alpha-synuclein (αSyn) aggregates are a typical feature of Parkinson's disease (PD). Extracellular insoluble αSyn can induce pathology in healthy neurons suggesting that PD neurodegeneration may spread through cell-to-cell transfer of αSyn proteopathic seeds. Early pro-homeostatic r...

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Autores: Sirerol-Piquer, Mª Salomé, Pérez-Villalba, Ana, Duart-Abadia, Pere, Belenguer, Germán, Gómez-Pinedo, Ulises, Blasco-Chamarro, Laura, Carrillo-Barberà, Pau, Pérez-Cañamás, Azucena, Navarro-Garrido, Victoria, Dehay, Benjamin, Vila, Miquel, Vitorica, Javier, Pérez-Sánchez, Francisco, Fariñas, Isabel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/390433
Acceso en línea:http://hdl.handle.net/10261/390433
https://api.elsevier.com/content/abstract/scopus_id/86000054106
Access Level:acceso abierto
Palabra clave:Aging
Alpha-synuclein
CSF
Lewy bodies
Microglia
PFFs
Parkinson’s disease
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spelling Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic speciesSirerol-Piquer, Mª SaloméPérez-Villalba, AnaDuart-Abadia, PereBelenguer, GermánGómez-Pinedo, UlisesBlasco-Chamarro, LauraCarrillo-Barberà, PauPérez-Cañamás, AzucenaNavarro-Garrido, VictoriaDehay, BenjaminVila, MiquelVitorica, JavierPérez-Sánchez, FranciscoFariñas, IsabelAgingAlpha-synucleinCSFLewy bodiesMicrogliaPFFsParkinson’s diseaseCytoplasmic alpha-synuclein (αSyn) aggregates are a typical feature of Parkinson's disease (PD). Extracellular insoluble αSyn can induce pathology in healthy neurons suggesting that PD neurodegeneration may spread through cell-to-cell transfer of αSyn proteopathic seeds. Early pro-homeostatic reaction of microglia to toxic forms of αSyn remains elusive, which is especially relevant considering the recently uncovered microglial molecular diversity. Here, we show that periventricular microglia of the subependymal neurogenic niche monitor the cerebrospinal fluid and can rapidly phagocytize and degrade different aggregated forms of αSyn delivered into the lateral ventricle. However, this clearing ability worsens with age, leading to an increase in microglia with aggregates in aged treated mice, an accumulation also observed in human PD samples. We also show that exposure of aged microglia to aggregated αSyn isolated from human PD samples results in the phosphorylation of the endogenous protein and the generation of αSyn seeds that can transmit the pathology to healthy neurons. Our data indicate that while microglial phagocytosis rapidly clears toxic αSyn, aged microglia can contribute to synucleinopathy spreading.We thank M. J. Palop for help with the mouse colonies and technical assistance and acknowledge the support of the Servicio Central de Soporte a la Investigación Experimental (SCSIE-UVEG). This work was supported by grants PID2020-117937GB-I00, RED2018-102723-T, and CB06/05/0086 (CIBERNED) from Ministerio de Ciencia e Innovación (MICINN) and Prometeo 2021/028 from Generalitat Valenciana to I.F. P.D-A. is a recipient of a MICINN’s FPI predoctoral contract, and L.B.-C. was a recipient of an FPU predoctoral contract from Ministerio de Universidades. This study received financial support from the French government in the framework of the University of Bordeaux’s IdEx “Investments for the Future” program/GPR BRAIN_2030.Peer reviewedBioMed CentralUniversidad de ValenciaAgencia Estatal de Investigación (España)Ministerio de Ciencia e Innovación (España)Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)Generalitat ValencianaMinisterio de Ciencia, Innovación y Universidades (España)Université de BordeauxGouvernement de la République françaiseFariñas, Isabel [0000-0003-2903-4960]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/390433https://api.elsevier.com/content/abstract/scopus_id/86000054106reponame: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/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-117937GB-I00info:eu-repo/grantAgreement/AEI//RED2018-102723-TThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1186/s13024-025-00816-1https://doi.org/10.1186/s13024-025-00816-1Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3904332026-05-22T06:33:51Z
dc.title.none.fl_str_mv Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species
title Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species
spellingShingle Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species
Sirerol-Piquer, Mª Salomé
Aging
Alpha-synuclein
CSF
Lewy bodies
Microglia
PFFs
Parkinson’s disease
title_short Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species
title_full Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species
title_fullStr Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species
title_full_unstemmed Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species
title_sort Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species
dc.creator.none.fl_str_mv Sirerol-Piquer, Mª Salomé
Pérez-Villalba, Ana
Duart-Abadia, Pere
Belenguer, Germán
Gómez-Pinedo, Ulises
Blasco-Chamarro, Laura
Carrillo-Barberà, Pau
Pérez-Cañamás, Azucena
Navarro-Garrido, Victoria
Dehay, Benjamin
Vila, Miquel
Vitorica, Javier
Pérez-Sánchez, Francisco
Fariñas, Isabel
author Sirerol-Piquer, Mª Salomé
author_facet Sirerol-Piquer, Mª Salomé
Pérez-Villalba, Ana
Duart-Abadia, Pere
Belenguer, Germán
Gómez-Pinedo, Ulises
Blasco-Chamarro, Laura
Carrillo-Barberà, Pau
Pérez-Cañamás, Azucena
Navarro-Garrido, Victoria
Dehay, Benjamin
Vila, Miquel
Vitorica, Javier
Pérez-Sánchez, Francisco
Fariñas, Isabel
author_role author
author2 Pérez-Villalba, Ana
Duart-Abadia, Pere
Belenguer, Germán
Gómez-Pinedo, Ulises
Blasco-Chamarro, Laura
Carrillo-Barberà, Pau
Pérez-Cañamás, Azucena
Navarro-Garrido, Victoria
Dehay, Benjamin
Vila, Miquel
Vitorica, Javier
Pérez-Sánchez, Francisco
Fariñas, Isabel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Valencia
Agencia Estatal de Investigación (España)
Ministerio de Ciencia e Innovación (España)
Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)
Generalitat Valenciana
Ministerio de Ciencia, Innovación y Universidades (España)
Université de Bordeaux
Gouvernement de la République française
Fariñas, Isabel [0000-0003-2903-4960]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Aging
Alpha-synuclein
CSF
Lewy bodies
Microglia
PFFs
Parkinson’s disease
topic Aging
Alpha-synuclein
CSF
Lewy bodies
Microglia
PFFs
Parkinson’s disease
description Cytoplasmic alpha-synuclein (αSyn) aggregates are a typical feature of Parkinson's disease (PD). Extracellular insoluble αSyn can induce pathology in healthy neurons suggesting that PD neurodegeneration may spread through cell-to-cell transfer of αSyn proteopathic seeds. Early pro-homeostatic reaction of microglia to toxic forms of αSyn remains elusive, which is especially relevant considering the recently uncovered microglial molecular diversity. Here, we show that periventricular microglia of the subependymal neurogenic niche monitor the cerebrospinal fluid and can rapidly phagocytize and degrade different aggregated forms of αSyn delivered into the lateral ventricle. However, this clearing ability worsens with age, leading to an increase in microglia with aggregates in aged treated mice, an accumulation also observed in human PD samples. We also show that exposure of aged microglia to aggregated αSyn isolated from human PD samples results in the phosphorylation of the endogenous protein and the generation of αSyn seeds that can transmit the pathology to healthy neurons. Our data indicate that while microglial phagocytosis rapidly clears toxic αSyn, aged microglia can contribute to synucleinopathy spreading.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
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/10261/390433
https://api.elsevier.com/content/abstract/scopus_id/86000054106
url http://hdl.handle.net/10261/390433
https://api.elsevier.com/content/abstract/scopus_id/86000054106
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/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-117937GB-I00
info:eu-repo/grantAgreement/AEI//RED2018-102723-T
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1186/s13024-025-00816-1
https://doi.org/10.1186/s13024-025-00816-1
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 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
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score 15,81155

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