Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology

Background: TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be dete...

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Autores: Suárez-Calvet, Marc, Morenas-Rodríguez, Estrella, Kleinberger, Gernot, Schlepckow, Kai, Araque Caballero, Miguel Ángel, Franzmeier, Nicolai, Capell, Anja, Fellerer, Katrin, Nuscher, Brigitte, Eren, E., Levin, Johannes, Deming, Yuetiva, Piccio, Laura, Karch, Celeste M., Cruchaga, Carlos, Shaw, Leslie M., Trojanowski, John Q., Weiner, Michael, Ewers, Michael, Haass, Christian
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/201459
Acceso en línea:http://hdl.handle.net/10261/201459
Access Level:acceso abierto
Palabra clave:Alzheimer’s disease
Biomarkers
Microglia
Neurodegeneration
Neuroinflammation
Shedding
TREM2
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oai_identifier_str oai:digital.csic.es:10261/201459
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology
title Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology
spellingShingle Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology
Suárez-Calvet, Marc
Alzheimer’s disease
Biomarkers
Microglia
Neurodegeneration
Neuroinflammation
Shedding
TREM2
title_short Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology
title_full Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology
title_fullStr Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology
title_full_unstemmed Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology
title_sort Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology
dc.creator.none.fl_str_mv Suárez-Calvet, Marc
Morenas-Rodríguez, Estrella
Kleinberger, Gernot
Schlepckow, Kai
Araque Caballero, Miguel Ángel
Franzmeier, Nicolai
Capell, Anja
Fellerer, Katrin
Nuscher, Brigitte
Eren, E.
Levin, Johannes
Deming, Yuetiva
Piccio, Laura
Karch, Celeste M.
Cruchaga, Carlos
Shaw, Leslie M.
Trojanowski, John Q.
Weiner, Michael
Ewers, Michael
Haass, Christian
author Suárez-Calvet, Marc
author_facet Suárez-Calvet, Marc
Morenas-Rodríguez, Estrella
Kleinberger, Gernot
Schlepckow, Kai
Araque Caballero, Miguel Ángel
Franzmeier, Nicolai
Capell, Anja
Fellerer, Katrin
Nuscher, Brigitte
Eren, E.
Levin, Johannes
Deming, Yuetiva
Piccio, Laura
Karch, Celeste M.
Cruchaga, Carlos
Shaw, Leslie M.
Trojanowski, John Q.
Weiner, Michael
Ewers, Michael
Haass, Christian
author_role author
author2 Morenas-Rodríguez, Estrella
Kleinberger, Gernot
Schlepckow, Kai
Araque Caballero, Miguel Ángel
Franzmeier, Nicolai
Capell, Anja
Fellerer, Katrin
Nuscher, Brigitte
Eren, E.
Levin, Johannes
Deming, Yuetiva
Piccio, Laura
Karch, Celeste M.
Cruchaga, Carlos
Shaw, Leslie M.
Trojanowski, John Q.
Weiner, Michael
Ewers, Michael
Haass, Christian
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv German Research Foundation
Munich Cluster for Systems Neurology
Association for Frontotemporal Degeneration (US)
European Commission
National Institutes of Health (US)
Fondazione Italiana Sclerosi Multipla
Sociedad Española de Neurología
Instituto de Salud Carlos III
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Alzheimer’s disease
Biomarkers
Microglia
Neurodegeneration
Neuroinflammation
Shedding
TREM2
topic Alzheimer’s disease
Biomarkers
Microglia
Neurodegeneration
Neuroinflammation
Shedding
TREM2
description Background: TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid β-peptide (Aβ) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD. Methods: A cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of Aβ (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score. Results: CSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal Aβ pathology (A+) but no tau pathology or neurodegeneration (TN-), is present. Conclusions: Aβ pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, Aβ pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
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/10261/201459
url http://hdl.handle.net/10261/201459
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/EC/H2020/752310
http://dx.doi.org/10.1186/s13024-018-0301-5
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
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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spelling Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathologySuárez-Calvet, MarcMorenas-Rodríguez, EstrellaKleinberger, GernotSchlepckow, KaiAraque Caballero, Miguel ÁngelFranzmeier, NicolaiCapell, AnjaFellerer, KatrinNuscher, BrigitteEren, E.Levin, JohannesDeming, YuetivaPiccio, LauraKarch, Celeste M.Cruchaga, CarlosShaw, Leslie M.Trojanowski, John Q.Weiner, MichaelEwers, MichaelHaass, ChristianAlzheimer’s diseaseBiomarkersMicrogliaNeurodegenerationNeuroinflammationSheddingTREM2Background: TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid β-peptide (Aβ) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD. Methods: A cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of Aβ (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score. Results: CSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal Aβ pathology (A+) but no tau pathology or neurodegeneration (TN-), is present. Conclusions: Aβ pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, Aβ pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.This work was supported by the Deutsche Forschungsgemeinschaft (DFG) within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy), a DFG funded Koselleck Project (HA1737/16-1 to CH) and the AFTD Biomarker Award (to MSC, JL, ME and CH). MSC received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310. This work was also supported by grants from the National Institutes of Health (R01AG044546, RF1AG053303, RF1AG058501, and U01AG058922), YD was supported by a NIMH institutional training grant (T32MH014877). LP was supported by a grant from the Fondazione Italiana Sclerosi Multipla (FISM 2017/R/20). EM was supported by a grant from the Ad-Hoc Committee for Young Neurologist (Spanish Society of Neurology) and Health Institute Carlos III (funding program for the mobility of the researchers).Springer NatureGerman Research FoundationMunich Cluster for Systems NeurologyAssociation for Frontotemporal Degeneration (US)European CommissionNational Institutes of Health (US)Fondazione Italiana Sclerosi MultiplaSociedad Española de NeurologíaInstituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/201459reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/752310http://dx.doi.org/10.1186/s13024-018-0301-5Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2014592026-05-22T06:33:51Z
score 15,812455

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