Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease

Background Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal...

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Autores: Visser, PJ, Reus, LM, Gobom, J, Jansen, I, Dicks, E, Van der Lee, SJ, Tsolaki, M, Verhey, FRJ, Popp, J, Martinez-Lage, P, Vandenberghe, R, Lleo, A, Molinuevo, JL, Engelborghs, S, Freund-Levi, Y, Froelich, L, Sleegers, K, Dobricic, V, Lovestone, S, Streffer, J, Vos, SJB, Bos, I, Smit, AB, Blennow, K, Scheltens, P, Teunissen, CE, Bertram, L, Zetterberg, H, Tijms, BM
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p8499
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=8499
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85127226284&doi=10.1186%2fs13024-022-00521-3&partnerID=40&md5=fbbe5699958ee91b7571bf3224a577c1
Access Level:acceso abierto
Palabra clave:Alzheimer's disease
Molecular mechanisms
Biomarker discovery
Heterogeneity
Neuronal plasticity
Cerebrospinal fluid proteomics
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spelling Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's diseaseVisser, PJReus, LMGobom, JJansen, IDicks, EVan der Lee, SJTsolaki, MVerhey, FRJPopp, JMartinez-Lage, PVandenberghe, RLleo, AMolinuevo, JLEngelborghs, SFreund-Levi, YFroelich, LSleegers, KDobricic, VLovestone, SStreffer, JVos, SJBBos, ISmit, ABBlennow, KScheltens, PTeunissen, CEBertram, LZetterberg, HTijms, BMAlzheimer's diseaseMolecular mechanismsBiomarker discoveryHeterogeneityNeuronal plasticityCerebrospinal fluid proteomicsBackground Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. Methods We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. Results We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. Conclusions CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.BMC2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=8499https://www.scopus.com/inward/record.uri?eid=2-s2.0-85127226284&doi=10.1186%2fs13024-022-00521-3&partnerID=40&md5=fbbe5699958ee91b7571bf3224a577c1Molecular NeurodegenerationISSN: 17501326reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p84992026-06-14T12:41:47Z
dc.title.none.fl_str_mv Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
title Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
spellingShingle Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
Visser, PJ
Alzheimer's disease
Molecular mechanisms
Biomarker discovery
Heterogeneity
Neuronal plasticity
Cerebrospinal fluid proteomics
title_short Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
title_full Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
title_fullStr Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
title_full_unstemmed Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
title_sort Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
dc.creator.none.fl_str_mv Visser, PJ
Reus, LM
Gobom, J
Jansen, I
Dicks, E
Van der Lee, SJ
Tsolaki, M
Verhey, FRJ
Popp, J
Martinez-Lage, P
Vandenberghe, R
Lleo, A
Molinuevo, JL
Engelborghs, S
Freund-Levi, Y
Froelich, L
Sleegers, K
Dobricic, V
Lovestone, S
Streffer, J
Vos, SJB
Bos, I
Smit, AB
Blennow, K
Scheltens, P
Teunissen, CE
Bertram, L
Zetterberg, H
Tijms, BM
author Visser, PJ
author_facet Visser, PJ
Reus, LM
Gobom, J
Jansen, I
Dicks, E
Van der Lee, SJ
Tsolaki, M
Verhey, FRJ
Popp, J
Martinez-Lage, P
Vandenberghe, R
Lleo, A
Molinuevo, JL
Engelborghs, S
Freund-Levi, Y
Froelich, L
Sleegers, K
Dobricic, V
Lovestone, S
Streffer, J
Vos, SJB
Bos, I
Smit, AB
Blennow, K
Scheltens, P
Teunissen, CE
Bertram, L
Zetterberg, H
Tijms, BM
author_role author
author2 Reus, LM
Gobom, J
Jansen, I
Dicks, E
Van der Lee, SJ
Tsolaki, M
Verhey, FRJ
Popp, J
Martinez-Lage, P
Vandenberghe, R
Lleo, A
Molinuevo, JL
Engelborghs, S
Freund-Levi, Y
Froelich, L
Sleegers, K
Dobricic, V
Lovestone, S
Streffer, J
Vos, SJB
Bos, I
Smit, AB
Blennow, K
Scheltens, P
Teunissen, CE
Bertram, L
Zetterberg, H
Tijms, BM
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimer's disease
Molecular mechanisms
Biomarker discovery
Heterogeneity
Neuronal plasticity
Cerebrospinal fluid proteomics
topic Alzheimer's disease
Molecular mechanisms
Biomarker discovery
Heterogeneity
Neuronal plasticity
Cerebrospinal fluid proteomics
description Background Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. Methods We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. Results We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. Conclusions CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.
publishDate 2022
dc.date.none.fl_str_mv 2022
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://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=8499
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85127226284&doi=10.1186%2fs13024-022-00521-3&partnerID=40&md5=fbbe5699958ee91b7571bf3224a577c1
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=8499
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85127226284&doi=10.1186%2fs13024-022-00521-3&partnerID=40&md5=fbbe5699958ee91b7571bf3224a577c1
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 Molecular Neurodegeneration
ISSN: 17501326
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
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