Progressive modulation of the human olfactory bulb transcriptome during Alzheimer´s disease evolution: novel insights into the olfactory signaling across proteinopathies
Fecha
2017Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Impacto
|
10.18632/oncotarget.18193
Resumen
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 ...
[++]
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. [--]
Materias
Alzheimer,
Neurodegeneration,
Dementia,
Olfactory bulb,
Transcriptomics
Editor
Impact Journals
Publicado en
Oncotarget, 2017, Vol. 8, (No. 41), pp: 69663-69679
Departamento
Universidad Pública de Navarra. Departamento de Ciencias de la Salud /
Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
Versión del editor
Entidades Financiadoras
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.
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