Research Papers:

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

Mercedes Lachen-Montes, María Victoria Zelaya, Víctor Segura, Joaquín Fernández-Irigoyen and Enrique Santamaría _

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Oncotarget. 2017; 8:69663-69679. https://doi.org/10.18632/oncotarget.18193

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Mercedes Lachen-Montes1,2, María Victoria Zelaya1,2,3, Víctor Segura2,4, Joaquín Fernández-Irigoyen1,2,5,* and Enrique Santamaría1,2,5,*

1Clinical Neuroproteomics Group, Navarrabiomed, Departamento de Salud, Universidad Pública de Navarra, Pamplona, Spain

2IDISNA, Navarra Institute for Health Research, Pamplona, Spain

3Pathological Anatomy Department, Navarra Hospital Complex, Pamplona, Spain

4Bioinformatics Unit, Center for Applied Medical Research, University of Navarra, Pamplona, Spain

5Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Departamento de Salud, Universidad Pública de Navarra, Pamplona, Spain

*These authors share senior authorship

Correspondence to:

Enrique Santamaría, email: [email protected]

Keywords: Alzheimer, neurodegeneration, dementia, olfactory bulb, transcriptomics

Received: January 21, 2017     Accepted: May 07, 2017     Published: May 23, 2017


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 stage-dependent 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 network-driven 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.

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