Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease

Tau hyperphosphorylation is the first step of neurofibrillary tangle (NFT) formation. In the present study, samples of the entorhinal cortex (EC) and frontal cortex area 8 (FC) of cases with NFT pathology classified as stages I-II, III-IV, and V-VI without comorbidities, and of middle-aged (MA) indi...

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Authors: Ferrer, Isidro (Ferrer Abizanda), Andrés Benito, Pol, Ausín, Karina, Pamplona, Reinald, Río Fernández, José Antonio del, Fernández Irigoyen, Joaquín, Santamaría, Enrique
Format: article
Status:Published version
Publication Date:2021
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/179131
Online Access:https://hdl.handle.net/2445/179131
Access Level:Open access
Keyword:Malaltia d'Alzheimer
Envelliment
Proteòmica
Cervell
Alzheimer's disease
Aging
Proteomics
Brain
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spelling Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's diseaseFerrer, Isidro (Ferrer Abizanda)Andrés Benito, PolAusín, KarinaPamplona, ReinaldRío Fernández, José Antonio delFernández Irigoyen, JoaquínSantamaría, EnriqueMalaltia d'AlzheimerEnvellimentProteòmicaCervellAlzheimer's diseaseAgingProteomicsBrainTau hyperphosphorylation is the first step of neurofibrillary tangle (NFT) formation. In the present study, samples of the entorhinal cortex (EC) and frontal cortex area 8 (FC) of cases with NFT pathology classified as stages I-II, III-IV, and V-VI without comorbidities, and of middle-aged (MA) individuals with no NFT pathology, were analyzed by conventional label-free and SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 214 in the EC, 65 of which were dysregulated at the first stages (I-II) of NFT pathology; 167 phosphoproteins were dysregulated in the FC, 81 of them at stages I-II of NFT pathology. A large percentage of dysregulated phosphoproteins were identified in the two regions and at different stages of NFT progression. The main group of dysregulated phosphoproteins was made up of components of the membranes, cytoskeleton, synapses, proteins linked to membrane transport and ion channels, and kinases. The present results show abnormal phosphorylation of proteins at the first stages of NFT pathology in the elderly (in individuals clinically considered representative of normal aging) and sporadic Alzheimer's disease (sAD). Dysregulated protein phosphorylation in the FC precedes the formation of NFTs and SPs. The most active period of dysregulated phosphorylation is at stages III-IV when a subpopulation of individuals might be clinically categorized as suffering from mild cognitive impairment which is a preceding determinant stage in the progression to dementia. Altered phosphorylation of selected proteins, carried out by activation of several kinases, may alter membrane and cytoskeletal functions, among them synaptic transmission and membrane/cytoskeleton signaling. Besides their implications in sAD, the present observations suggest a molecular substrate for "benign" cognitive deterioration in "normal" brain aging.Wiley2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/179131Articles publicats en revistes (Patologia i Terapèutica Experimental)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1111/bpa.12996Brain Pathology, 2021, vol. 31, num.6, e12996https://doi.org/10.1111/bpa.12996cc by-nc-nd (c) Ferrer, Isidro (Ferrer Abizanda) et al., 2021http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1791312026-05-27T06:46:51Z
dc.title.none.fl_str_mv Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease
title Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease
spellingShingle Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease
Ferrer, Isidro (Ferrer Abizanda)
Malaltia d'Alzheimer
Envelliment
Proteòmica
Cervell
Alzheimer's disease
Aging
Proteomics
Brain
title_short Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease
title_full Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease
title_fullStr Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease
title_full_unstemmed Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease
title_sort Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease
dc.creator.none.fl_str_mv Ferrer, Isidro (Ferrer Abizanda)
Andrés Benito, Pol
Ausín, Karina
Pamplona, Reinald
Río Fernández, José Antonio del
Fernández Irigoyen, Joaquín
Santamaría, Enrique
author Ferrer, Isidro (Ferrer Abizanda)
author_facet Ferrer, Isidro (Ferrer Abizanda)
Andrés Benito, Pol
Ausín, Karina
Pamplona, Reinald
Río Fernández, José Antonio del
Fernández Irigoyen, Joaquín
Santamaría, Enrique
author_role author
author2 Andrés Benito, Pol
Ausín, Karina
Pamplona, Reinald
Río Fernández, José Antonio del
Fernández Irigoyen, Joaquín
Santamaría, Enrique
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Malaltia d'Alzheimer
Envelliment
Proteòmica
Cervell
Alzheimer's disease
Aging
Proteomics
Brain
topic Malaltia d'Alzheimer
Envelliment
Proteòmica
Cervell
Alzheimer's disease
Aging
Proteomics
Brain
description Tau hyperphosphorylation is the first step of neurofibrillary tangle (NFT) formation. In the present study, samples of the entorhinal cortex (EC) and frontal cortex area 8 (FC) of cases with NFT pathology classified as stages I-II, III-IV, and V-VI without comorbidities, and of middle-aged (MA) individuals with no NFT pathology, were analyzed by conventional label-free and SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 214 in the EC, 65 of which were dysregulated at the first stages (I-II) of NFT pathology; 167 phosphoproteins were dysregulated in the FC, 81 of them at stages I-II of NFT pathology. A large percentage of dysregulated phosphoproteins were identified in the two regions and at different stages of NFT progression. The main group of dysregulated phosphoproteins was made up of components of the membranes, cytoskeleton, synapses, proteins linked to membrane transport and ion channels, and kinases. The present results show abnormal phosphorylation of proteins at the first stages of NFT pathology in the elderly (in individuals clinically considered representative of normal aging) and sporadic Alzheimer's disease (sAD). Dysregulated protein phosphorylation in the FC precedes the formation of NFTs and SPs. The most active period of dysregulated phosphorylation is at stages III-IV when a subpopulation of individuals might be clinically categorized as suffering from mild cognitive impairment which is a preceding determinant stage in the progression to dementia. Altered phosphorylation of selected proteins, carried out by activation of several kinases, may alter membrane and cytoskeletal functions, among them synaptic transmission and membrane/cytoskeleton signaling. Besides their implications in sAD, the present observations suggest a molecular substrate for "benign" cognitive deterioration in "normal" brain aging.
publishDate 2021
dc.date.none.fl_str_mv 2021
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://hdl.handle.net/2445/179131
url https://hdl.handle.net/2445/179131
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1111/bpa.12996
Brain Pathology, 2021, vol. 31, num.6, e12996
https://doi.org/10.1111/bpa.12996
dc.rights.none.fl_str_mv cc by-nc-nd (c) Ferrer, Isidro (Ferrer Abizanda) et al., 2021
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Ferrer, Isidro (Ferrer Abizanda) et al., 2021
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv Articles publicats en revistes (Patologia i Terapèutica Experimental)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869410972783869952
score 15.301603

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