Neuropathological stage-dependent proteome mapping of the olfactory tract in Alzheimer's disease: from early olfactory-related omics signatures to computational repurposing of drug candidates

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dc.contributor.authorCartas Cejudo, Paz
dc.contributor.authorCortés, Adriana
dc.contributor.authorLachén Montes, Mercedes
dc.contributor.authorAnaya-Cubero, Elena
dc.contributor.authorPuerta, Elena
dc.contributor.authorSolas, Maite
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.contributor.funderUniversidad Pública de Navarra / Nafarroako Unibertsitate Publikoa
dc.date.accessioned2024-09-03T17:01:45Z
dc.date.available2024-09-03T17:01:45Z
dc.date.issued2024
dc.date.updated2024-09-03T16:34:50Z
dc.description.abstractAlzheimer's disease (AD) is the most common form of dementia, characterized by an early olfactory dysfunction, progressive memory loss, and behavioral deterioration. Albeit substantial progress has been made in characterizing AD-associated molecular and cellular events, there is an unmet clinical need for new therapies. In this study, olfactory tract proteotyping performed in controls and AD subjects (n = 17/group) showed a Braak stage-dependent proteostatic impairment accompanied by the progressive modulation of amyloid precursor protein and tau functional interactomes. To implement a computational repurposing of drug candidates with the capacity to reverse early AD-related olfactory omics signatures (OMSs), we generated a consensual OMSs database compiling differential omics datasets obtained by mass-spectrometry or RNA-sequencing derived from initial AD across the olfactory axis. Using the Connectivity Map-based drug repurposing approach, PKC, EGFR, Aurora kinase, Glycogen synthase kinase, and CDK inhibitors were the top pharmacologic classes capable to restore multiple OMSs, whereas compounds with targeted activity to inhibit PI3K, Insulin-like growth factor 1 (IGF-1), microtubules, and Polo-like kinase (PLK) represented a family of drugs with detrimental potential to induce olfactory AD-associated gene expression changes. To validate the potential therapeutic effects of the proposed drugs, in vitro assays were performed. These validation experiments revealed that pretreatment of human neuron-like SH-SY5Y cells with the EGFR inhibitor AG-1478 showed a neuroprotective effect against hydrogen peroxide-induced damage while the pretreatment with the Aurora kinase inhibitor Reversine reduced amyloid-beta (Aβ)-induced neurotoxicity. Taken together, our data pointed out that OMSs may be useful as substrates for drug repurposing to propose novel neuroprotective treatments against AD.en
dc.description.sponsorshipSpanish Ministry of Science, Innovation and Universities, Grant/Award Number: PID2019-110356RB-I00/AEI/10.13039/501100011033; Department of Economic and Business Development from Government of Navarra, Grant/Award Number: 0011-1411-2023-000028; Public University of Navarra (UPNA); Miguel Servet Foundation-Navarrabiomed; Programa MRR Investigo 2023
dc.format.mimetypeapplication/pdfen
dc.identifier.citationCartas-Cejudo, P., Cortés, A., Lachén-Montes, M., Anaya-Cubero, E., Puerta, E., Solas, M., Fernández-Irigoyen, J., Santamaría, E. (2024) Neuropathological stage-dependent proteome mapping of the olfactory tract in Alzheimer's disease: from early olfactory-related omics signatures to computational repurposing of drug candidates. Brain Pathology, 34(4), e13252. https://doi.org/10.1111/bpa.13252.
dc.identifier.doi10.1111/bpa.13252
dc.identifier.issn1015-6305
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/51532
dc.language.isoeng
dc.publisherWiley
dc.relation.ispartofBrain Pathology 2024, 34(4), e13252
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//0011-1411-2023-000028/
dc.relation.publisherversionhttps://doi.org/10.1111/bpa.13252
dc.rights© 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectConnectivity Mapen
dc.subjectDrug repurposingen
dc.subjectOlfactory tracten
dc.subjectProteomicsen
dc.titleNeuropathological stage-dependent proteome mapping of the olfactory tract in Alzheimer's disease: from early olfactory-related omics signatures to computational repurposing of drug candidatesen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
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