Protein tau phosphorylation in the proline rich region and its implication in the progression of Alzheimer's disease

Tau has a wide variety of essential functions in the brain, but this protein also plays a determining role in the development of Alzheimer's disease (AD) and other neurodegenerative diseases called tauopathies. This is due to its abnormal aggregation and the subsequent formation of neurofibrill...

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Autores: Merino-Serrais, Paula, Soria, José Miguel, Arrabal, Cristina Aguirre, Ortigado-López, Alfonso, Esparza, María Ángeles García, Muñoz, Alberto, Hernández, Félix, Ávila, Jesús, DeFelipe, Javier, León-Espinosa, Gonzalo
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:10261/404013
Acceso en línea:http://hdl.handle.net/10261/404013
https://api.elsevier.com/content/abstract/scopus_id/85208758184
Access Level:acceso abierto
Palabra clave:Colocalization
P301S transgenic mice
Immunocytochemistry
hippocampus.
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
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oai_identifier_str oai:digital.csic.es:10261/404013
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Protein tau phosphorylation in the proline rich region and its implication in the progression of Alzheimer's disease
title Protein tau phosphorylation in the proline rich region and its implication in the progression of Alzheimer's disease
spellingShingle Protein tau phosphorylation in the proline rich region and its implication in the progression of Alzheimer's disease
Merino-Serrais, Paula
Colocalization
P301S transgenic mice
Immunocytochemistry
hippocampus.
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
title_short Protein tau phosphorylation in the proline rich region and its implication in the progression of Alzheimer's disease
title_full Protein tau phosphorylation in the proline rich region and its implication in the progression of Alzheimer's disease
title_fullStr Protein tau phosphorylation in the proline rich region and its implication in the progression of Alzheimer's disease
title_full_unstemmed Protein tau phosphorylation in the proline rich region and its implication in the progression of Alzheimer's disease
title_sort Protein tau phosphorylation in the proline rich region and its implication in the progression of Alzheimer's disease
dc.creator.none.fl_str_mv Merino-Serrais, Paula
Soria, José Miguel
Arrabal, Cristina Aguirre
Ortigado-López, Alfonso
Esparza, María Ángeles García
Muñoz, Alberto
Hernández, Félix
Ávila, Jesús
DeFelipe, Javier
León-Espinosa, Gonzalo
author Merino-Serrais, Paula
author_facet Merino-Serrais, Paula
Soria, José Miguel
Arrabal, Cristina Aguirre
Ortigado-López, Alfonso
Esparza, María Ángeles García
Muñoz, Alberto
Hernández, Félix
Ávila, Jesús
DeFelipe, Javier
León-Espinosa, Gonzalo
author_role author
author2 Soria, José Miguel
Arrabal, Cristina Aguirre
Ortigado-López, Alfonso
Esparza, María Ángeles García
Muñoz, Alberto
Hernández, Félix
Ávila, Jesús
DeFelipe, Javier
León-Espinosa, Gonzalo
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de San Pablo-CEU
Banco Santander
Cajal Blue Brain
Instituto de Salud Carlos III
Ministerio de Ciencia e Innovación (España)
Ministerio de Economía y Competitividad (España)
0000-0001-5484-0660
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Colocalization
P301S transgenic mice
Immunocytochemistry
hippocampus.
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
topic Colocalization
P301S transgenic mice
Immunocytochemistry
hippocampus.
http://metadata.un.org/sdg/3
Ensure healthy lives and promote well-being for all at all ages
description Tau has a wide variety of essential functions in the brain, but this protein also plays a determining role in the development of Alzheimer's disease (AD) and other neurodegenerative diseases called tauopathies. This is due to its abnormal aggregation and the subsequent formation of neurofibrillary tangles. Tau hyperphosphorylation appears to be a critical step in its transformation into an aggregated protein. However, the exact process, including the cellular events that trigger it, remains unclear. In this study, we employed immunocytochemistry assays on hippocampal sections from AD cases and from tauopathy cases (Braak stage III) with no evidence of cognitive decline, and the P301S mouse model to investigate the colocalization patterns of Tau phosphorylated (p) at specific residues (S202-T205, S214, and T231) within the proline-rich region. Our results show pyramidal neurons in the hippocampus of P301S mice in which Tau is intensely phosphorylated at residues S202 and T205 (recognized by the AT8 antibody), but with no detectable phosphorylation at S214 or T231. These non-colocalizing neurons displayed intensely labeled aggregated pTau deposits distributed through the soma and dendritic processes. However, most of the hippocampal pyramidal neurons are labeled with pTauS214 or pTauT231 antibodies and typically showed a homogeneous and diffuse pTau distribution (not aggregated). This different labeling likely reflects a Tau conformational step, potentially related to the transition from a diffuse tau phosphorylation phenotype (Type 2) into an NFT-like or Type 1 phenotype. We further observed that dendrites of CA3 pyramidal cells are intensely labeled with pTau214 in the stratum lucidum, but not with AT8 or pTauT231. By contrast, analysis of tissue from AD patients or other human tauopathy cases (Braak stage III) with no evidence of cognitive decline revealed extensive colocalization with both antibody combinations in CA1. The complete or mature tangle development may follow a different mechanism in the P301S mouse model or may require more time to achieve the maturity state found in AD cases. Further studies would be necessary to address this question.
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/10261/404013
https://api.elsevier.com/content/abstract/scopus_id/85208758184
url http://hdl.handle.net/10261/404013
https://api.elsevier.com/content/abstract/scopus_id/85208758184
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-123859OB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-113204GB-I00
Experimental neurology
https://doi.org/10.1016/j.expneurol.2024.115049
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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
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spelling Protein tau phosphorylation in the proline rich region and its implication in the progression of Alzheimer's diseaseMerino-Serrais, PaulaSoria, José MiguelArrabal, Cristina AguirreOrtigado-López, AlfonsoEsparza, María Ángeles GarcíaMuñoz, AlbertoHernández, FélixÁvila, JesúsDeFelipe, JavierLeón-Espinosa, GonzaloColocalizationP301S transgenic miceImmunocytochemistryhippocampus.http://metadata.un.org/sdg/3Ensure healthy lives and promote well-being for all at all agesTau has a wide variety of essential functions in the brain, but this protein also plays a determining role in the development of Alzheimer's disease (AD) and other neurodegenerative diseases called tauopathies. This is due to its abnormal aggregation and the subsequent formation of neurofibrillary tangles. Tau hyperphosphorylation appears to be a critical step in its transformation into an aggregated protein. However, the exact process, including the cellular events that trigger it, remains unclear. In this study, we employed immunocytochemistry assays on hippocampal sections from AD cases and from tauopathy cases (Braak stage III) with no evidence of cognitive decline, and the P301S mouse model to investigate the colocalization patterns of Tau phosphorylated (p) at specific residues (S202-T205, S214, and T231) within the proline-rich region. Our results show pyramidal neurons in the hippocampus of P301S mice in which Tau is intensely phosphorylated at residues S202 and T205 (recognized by the AT8 antibody), but with no detectable phosphorylation at S214 or T231. These non-colocalizing neurons displayed intensely labeled aggregated pTau deposits distributed through the soma and dendritic processes. However, most of the hippocampal pyramidal neurons are labeled with pTauS214 or pTauT231 antibodies and typically showed a homogeneous and diffuse pTau distribution (not aggregated). This different labeling likely reflects a Tau conformational step, potentially related to the transition from a diffuse tau phosphorylation phenotype (Type 2) into an NFT-like or Type 1 phenotype. We further observed that dendrites of CA3 pyramidal cells are intensely labeled with pTau214 in the stratum lucidum, but not with AT8 or pTauT231. By contrast, analysis of tissue from AD patients or other human tauopathy cases (Braak stage III) with no evidence of cognitive decline revealed extensive colocalization with both antibody combinations in CA1. The complete or mature tangle development may follow a different mechanism in the P301S mouse model or may require more time to achieve the maturity state found in AD cases. Further studies would be necessary to address this question.This work was supported by a grant from Fundación Universitaria San Pablo CEU-Banco Santander to GLE (FUSP-PPC-19-264E8B2F) and from the following grants to JDF: PID2021-127924NB-I00 funded by MCIN/ AEI/10.13039/501100011033; CSIC Interdisciplinary Thematic Platform - Cajal Blue Brain (PTI-BLUEBRAIN; Spain); and CIBERNED, ISCIII, CB06/05/0066. Work in the laboratory of JA is funded by grants from MCIN/AEI/10.13039/501100011033/FEDER, UE (PID2021- 123859OB-100). Work in the laboratory of FH is funded by grants from the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía, Industria y Competitividad, Gobierno de España, PID2020- 113204GB-I00).Peer reviewedElsevierUniversidad de San Pablo-CEUBanco SantanderCajal Blue BrainInstituto de Salud Carlos IIIMinisterio de Ciencia e Innovación (España)Ministerio de Economía y Competitividad (España)0000-0001-5484-0660Consejo 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/publishedVersionhttp://hdl.handle.net/10261/404013https://api.elsevier.com/content/abstract/scopus_id/85208758184reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-127924NB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-123859OB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-113204GB-I00Experimental neurologyhttps://doi.org/10.1016/j.expneurol.2024.115049Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4040132026-05-22T06:33:51Z
score 15,811543

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