Proteostatic modulation in brain aging without associated Alzheimer's disease-and age-related neuropathological changes

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dc.contributor.authorAndrés Benito, Pol
dc.contributor.authorÍñigo-Marco, Ignacio
dc.contributor.authorBrullas, Marta
dc.contributor.authorCarmona, Margarita
dc.contributor.authorRío, José Antonio del
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorPovedano, Mónica
dc.contributor.authorFerrer, Isidro
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2023-11-08T12:25:49Z
dc.date.available2023-11-08T12:25:49Z
dc.date.issued2023
dc.date.updated2023-11-08T12:12:54Z
dc.description.abstractAims: (Phospho)proteomics of old-aged subjects without cognitive or behavioral symptoms, and without ADneuropathological changes and lacking any other neurodegenerative alteration will increase understanding about the physiological state of human brain aging without associate neurological deficits and neuropathological lesions. Methods: (Phospho)proteomics using conventional label-free- and SWATH-MS (Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) has been assessed in the frontal cortex (FC) of individuals without NFTs, senile plaques (SPs) and age-related co-morbidities classified by age (years) in four groups; group 1 (young, 30–44); group 2 (middle-aged: MA, 45-52); group 3 (early-elderly, 64–70); and group 4 (late-elderly, 75–85). Results: Protein levels and deregulated protein phosphorylation linked to similar biological terms/functions, but involving different individual proteins, are found in FC with age. The modified expression occurs in cytoskeleton proteins, membranes, synapses, vesicles, myelin, membrane transport and ion channels, DNA and RNA metabolism, ubiquitin-proteasome-system (UPS), kinases and phosphatases, fatty acid metabolism, and mitochondria. Dysregulated phosphoproteins are associated with the cytoskeleton, including microfilaments, actin-binding proteins, intermediate filaments of neurons and glial cells, and microtubules; membrane proteins, synapses, and dense core vesicles; kinases and phosphatases; proteins linked to DNA and RNA; members of the UPS; GTPase regulation; inflammation; and lipid metabolism. Noteworthy, protein levels of large clusters of hierarchically-related protein expression levels are stable until 70. However, protein levels of components of cell membranes, vesicles and synapses, RNA modulation, and cellular structures (including tau and tubulin filaments) are markedly altered from the age of 75. Similarly, marked modifications occur in the larger phosphoprotein clusters involving cytoskeleton and neuronal structures, membrane stabilization, and kinase regulation in the late elderly. Conclusions: Present findings may increase understanding of human brain proteostasis modifications in the elderly in the subpopulation of individuals not having AD neuropathological change and any other neurodegenerative change in any telencephalon region.en
dc.description.sponsorshipThe project leading to these results received funding from the “la Caixa” Foundation (ID 100010434) under the agreement LCF/PR/HR19/52160007, HR18-00452 to IF and JAdR. We thank CERCA Programme/Generalitat de Catalunya for institutional support. The Proteomics Platform of Navarrabiomed is a member of Proteored (PRB3-ISCIII) and is supported by grant PT17/0019/009 to JFI, of the PE I+D+I 2013–2016 funded by ISCIII and FEDER. Parts of this work were funded by a grant from the Spanish Ministry of Science Innovation and Universities (Ref. PID2019-110356RB-I00) to JFI and ES, and the Department of Economic and Business Development of the Government of Navarra (Ref. 0011- 1411-2020-000028) to ES.es_ES
dc.format.mimetypeapplication/pdfen
dc.identifier.citationAndrés-Benito, P., Íñigo-Marco, I., Brullas, M., Carmona, M., Rio, J. A. D., Fernández-Irigoyen, J., Santamaría, E., Povedano, M., & Ferrer, I. (2023). Proteostatic modulation in brain aging without associated Alzheimer’s disease-and age-related neuropathological changes. Aging, 15(9), 3295-3330. https://doi.org/10.18632/aging.204698en
dc.identifier.doi10.18632/aging.204698
dc.identifier.issn1945-4589
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/46729
dc.language.isoengen
dc.publisherImpact Journalsen
dc.relation.ispartofAging, 15(9) 3295-3330en
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110356RB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//0011- 1411-2020-000028/
dc.relation.publisherversionhttps://doi.org/10.18632/aging.204698
dc.rights© 2023 Andrés-Benito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/
dc.subject(Phospho)Proteomicsen
dc.subjectBrain agingen
dc.subjectCytoskeletonen
dc.subjectKinasesen
dc.subjectMembranesen
dc.subjectMitochondriaen
dc.subjectProteomeen
dc.subjectSynapsisen
dc.titleProteostatic modulation in brain aging without associated Alzheimer's disease-and age-related neuropathological changesen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication.latestForDiscovery86d1b76e-4790-40b1-a3ec-72331c5c6199

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