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Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease

BACKGROUND: Presenilin-1 (PS1), the active component of the intramembrane γ-secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The aim of this study was to examine the different soluble PS1 complexes in the lumbar CSF (CSF-PS1) of individuals with Alzh...

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Autores principales: Sogorb-Esteve, Aitana, García-Ayllón, María-Salud, Fortea, Juan, Sánchez-Valle, Raquel, Lleó, Alberto, Molinuevo, José-Luis, Sáez-Valero, Javier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043603/
https://www.ncbi.nlm.nih.gov/pubmed/27686161
http://dx.doi.org/10.1186/s13024-016-0131-2
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author Sogorb-Esteve, Aitana
García-Ayllón, María-Salud
Fortea, Juan
Sánchez-Valle, Raquel
Lleó, Alberto
Molinuevo, José-Luis
Sáez-Valero, Javier
author_facet Sogorb-Esteve, Aitana
García-Ayllón, María-Salud
Fortea, Juan
Sánchez-Valle, Raquel
Lleó, Alberto
Molinuevo, José-Luis
Sáez-Valero, Javier
author_sort Sogorb-Esteve, Aitana
collection PubMed
description BACKGROUND: Presenilin-1 (PS1), the active component of the intramembrane γ-secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The aim of this study was to examine the different soluble PS1 complexes in the lumbar CSF (CSF-PS1) of individuals with Alzheimer’s disease (AD), particularly in both symptomatic and asymptomatic genetically determined AD, in order to evaluate their potential as early biomarkers. METHODS: Western blotting, differential centrifugation and co-immunoprecipitation served to determine and characterize CSF-PS1 complexes. We also monitored the assembly of soluble PS1 into complexes in a cell model, and the participation of Aβ in the dynamics and robustness of the stable PS1 complexes. RESULTS: There was an age-dependent increase in CSF-PS1 levels in cognitively normal controls, the different complexes represented in similar proportions. The total levels of CSF-PS1, and in particular the proportion of the stable 100–150 kDa complexes, increased in subjects with autosomal dominant AD that carried PSEN1 mutations (eight symptomatic and six asymptomatic ADAD) and in Down syndrome individuals (ten demented and ten non-demented DS), compared with age-matched controls (n = 23), even prior to the appearance of symptoms of dementia. The proportion of stable CSF-PS1 complexes also increased in sporadic AD (n = 13) and mild-cognitive impaired subjects (n = 12), relative to age-matched controls (n = 17). Co-immunoprecipitation demonstrated the association of Aβ oligomers with soluble PS1 complexes, particularly the stable complexes. CONCLUSIONS: Our data suggest that CSF-PS1 complexes may be useful as an early biomarker for AD, reflecting the pathology at asymptomatic state. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0131-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-50436032016-10-05 Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease Sogorb-Esteve, Aitana García-Ayllón, María-Salud Fortea, Juan Sánchez-Valle, Raquel Lleó, Alberto Molinuevo, José-Luis Sáez-Valero, Javier Mol Neurodegener Research Article BACKGROUND: Presenilin-1 (PS1), the active component of the intramembrane γ-secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The aim of this study was to examine the different soluble PS1 complexes in the lumbar CSF (CSF-PS1) of individuals with Alzheimer’s disease (AD), particularly in both symptomatic and asymptomatic genetically determined AD, in order to evaluate their potential as early biomarkers. METHODS: Western blotting, differential centrifugation and co-immunoprecipitation served to determine and characterize CSF-PS1 complexes. We also monitored the assembly of soluble PS1 into complexes in a cell model, and the participation of Aβ in the dynamics and robustness of the stable PS1 complexes. RESULTS: There was an age-dependent increase in CSF-PS1 levels in cognitively normal controls, the different complexes represented in similar proportions. The total levels of CSF-PS1, and in particular the proportion of the stable 100–150 kDa complexes, increased in subjects with autosomal dominant AD that carried PSEN1 mutations (eight symptomatic and six asymptomatic ADAD) and in Down syndrome individuals (ten demented and ten non-demented DS), compared with age-matched controls (n = 23), even prior to the appearance of symptoms of dementia. The proportion of stable CSF-PS1 complexes also increased in sporadic AD (n = 13) and mild-cognitive impaired subjects (n = 12), relative to age-matched controls (n = 17). Co-immunoprecipitation demonstrated the association of Aβ oligomers with soluble PS1 complexes, particularly the stable complexes. CONCLUSIONS: Our data suggest that CSF-PS1 complexes may be useful as an early biomarker for AD, reflecting the pathology at asymptomatic state. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0131-2) contains supplementary material, which is available to authorized users. BioMed Central 2016-09-29 /pmc/articles/PMC5043603/ /pubmed/27686161 http://dx.doi.org/10.1186/s13024-016-0131-2 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Sogorb-Esteve, Aitana
García-Ayllón, María-Salud
Fortea, Juan
Sánchez-Valle, Raquel
Lleó, Alberto
Molinuevo, José-Luis
Sáez-Valero, Javier
Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease
title Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease
title_full Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease
title_fullStr Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease
title_full_unstemmed Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease
title_short Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease
title_sort cerebrospinal fluid presenilin-1 increases at asymptomatic stage in genetically determined alzheimer’s disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043603/
https://www.ncbi.nlm.nih.gov/pubmed/27686161
http://dx.doi.org/10.1186/s13024-016-0131-2
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