Progressive modulation of the human olfactory bulb transcriptome during Alzheimer´s disease evolution: novel insights into the olfactory signaling across proteinopathies

Lachén Montes, Mercedes; Zelaya Huerta, María Victoria; Segura, Víctor; Fernández Irigoyen, Joaquín; Santamaría Martínez, Enrique

Progressive modulation of the human olfactory bulb transcriptome during Alzheimer´s disease evolution: novel insights into the olfactory signaling across proteinopathies

dc.contributor.author	Lachén Montes, Mercedes
dc.contributor.author	Zelaya Huerta, María Victoria
dc.contributor.author	Segura, Víctor
dc.contributor.author	Fernández Irigoyen, Joaquín
dc.contributor.author	Santamaría Martínez, Enrique
dc.contributor.department	Ciencias de la Salud	es_ES
dc.contributor.department	Osasun Zientziak	eu
dc.contributor.funder	Gobierno de Navarra / Nafarroako Gobernua, PC025	es
dc.contributor.funder	Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa	es
dc.date.accessioned	2019-01-22T13:34:44Z
dc.date.available	2019-01-22T13:34:44Z
dc.date.issued	2017
dc.description.abstract	Alzheimer´s disease (AD) is characterized by progressive dementia, initially presenting olfactory dysfunction. Despite the olfactory bulb (OB) is the first central structure of the olfactory pathway, we lack a complete molecular characterization of the transcriptional events that occurs in this olfactory area during AD progression. To address this gap in knowledge, we have assessed the genome-wide expression in postmortem OBs from subjects with varying degree of AD pathology. A stagedependent deregulation of specific pathways was observed, revealing transmembrane transport, and neuroinflammation as part of the functional modules that are disrupted across AD grading. Potential drivers of neurodegeneration predicted by networkdriven transcriptomics were monitored across different types of dementia, including progressive supranuclear palsy (PSP), mixed dementia, and frontotemporal lobar degeneration (FTLD). Epidermal growth factor receptor (EGFR) expression was significantly increased in the OB of AD and mixed dementia subjects. Moreover, a significant increment in the activation of signal transducer and activator of transcription 3 (STAT3) was exclusively detected in advanced AD stages, whereas total STAT3 levels were specifically overexpressed in mixed dementia. Furthermore, transcription factors deregulated in the OB of mixed dementia subjects such as cAMP Responsive Element Binding Protein 1 (CREB1) and AP-1 Transcription Factor Subunit (c-Jun) were not differentially modulated at olfactory level across AD grading. On the other hand, olfactory expression of this signal transducer panel was unchanged in PSP and FTLD subjects. Taken together, this study unveils cross-disease similarities and differences for specific signal transducers, providing mechanistic clues to the intriguing divergence of AD pathology across proteinopathies.	en
dc.description.sponsorship	This work was funded by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (Ref. SAF2014-59340-R), Department of Economic Development from Government of Navarra (Ref. PC025), and Obra Social la Caixa to ES. MLM is supported by a predoctoral fellowship from the Public University of Navarra. The Proteomics Unit of Navarrabiomed is a member of Proteored, PRB2-ISCIII, and is supported by grant PT13/0001, of the PE I+D+I 2013-2016 funded by ISCIII and FEDER.	en
dc.format.extent	17 p.
dc.format.mimetype	application/pdf	en
dc.format.mimetype	application/zip	en
dc.identifier.doi	10.18632/oncotarget.18193
dc.identifier.issn	1949-2553 (Electronic)
dc.identifier.uri	https://academica-e.unavarra.es/handle/2454/32048
dc.language.iso	eng	en
dc.publisher	Impact Journals	en
dc.relation.ispartof	Oncotarget, 2017, Vol. 8, (No. 41), pp: 69663-69679	en
dc.relation.projectID	info:eu-repo/grantAgreement/MINECO//SAF2014-59340-R/ES/
dc.relation.publisherversion	https://doi.org/10.18632/oncotarget.18193
dc.rights	© Lachen-Montes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.	en
dc.rights.accessRights	info:eu-repo/semantics/openAccess
dc.rights.uri	https://creativecommons.org/licenses/by/3.0/
dc.subject	Alzheimer	en
dc.subject	Neurodegeneration	en
dc.subject	Dementia	en
dc.subject	Olfactory bulb	en
dc.subject	Transcriptomics	en
dc.title	Progressive modulation of the human olfactory bulb transcriptome during Alzheimer´s disease evolution: novel insights into the olfactory signaling across proteinopathies	en
dc.type	info:eu-repo/semantics/article
dc.type.version	info:eu-repo/semantics/publishedVersion
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