Research Papers: Gerotarget (Focus on Aging):

Olfactory bulb proteome dynamics during the progression of sporadic Alzheimer’s disease: identification of common and distinct olfactory targets across Alzheimer-related co-pathologies

María Victoria Zelaya, Estela Pérez-Valderrama, Xabier Martínez de Morentin, Teresa Tuñon, Isidro Ferrer, María Rosario Luquin, Joaquín Fernandez-Irigoyen and Enrique Santamaría _

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Oncotarget. 2015; 6:39437-39456. https://doi.org/10.18632/oncotarget.6254

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María Victoria Zelaya1, Estela Pérez-Valderrama1, Xabier Martínez de Morentin1, Teresa Tuñon2, Isidro Ferrer3, María Rosario Luquin4, Joaquín Fernandez-Irigoyen1,* and Enrique Santamaría1,*

1 Proteomics Unit, Clinical Neuroproteomics Group, Navarrabiomed, Fundación Miguel Servet, Proteored-ISCIII, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

2 Pathological Anatomy Department, Navarra Hospital Complex, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

3 Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Spain, CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Spain

4 Laboratory of Regenerative Therapy, Department of Neurology and Neuroscience Division, Centre for Applied Medical Research (CIMA), University of Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

* These authors share senior authorship

Correspondence to:

Enrique Santamaría, email:

Keywords: Alzheimer, neurodegeneration, olfactory bulb, proteomics, Gerotarget

Received: July 16, 2015 Accepted: September 30, 2015 Published: October 28, 2015


Olfactory dysfunction is present in up to 90% of Alzheimer’s disease (AD) patients. Although deposition of hyperphosphorylated tau and β-amyloid substrates are present in olfactory areas, the molecular mechanisms associated with decreased smell function are not completely understood. We have applied mass spectrometry-based quantitative proteomics to probe additional molecular disturbances in postmortem olfactory bulbs (OB) dissected from AD cases respect to neurologically intact controls (n=20, mean age 82.1 years). Relative proteome abundance measurements have revealed protein interaction networks progressively disturbed across AD stages suggesting an early imbalance in splicing factors, subsequent interrupted cycling of neurotransmitters, alteration in toxic and protective mechanisms of β-amyloid, and finally, a mitochondrial dysfunction together with disturbance in neuron-neuron adhesion. We also present novel molecular findings in the OB in an autopsy cohort composed by Lewy body disease (LBD), frontotemporal lobar degeneration (FTLD), mixed dementia, and progressive supranuclear palsy (PSP) cases (n = 41, mean age 79.7 years). Olfactory mediators deregulated during the progression of AD such as Visinin-like protein 1, RUFY3 protein, and Copine 6 were also differentially modulated in the OB in LBD, FTLD, and mixed dementia. Only Dipeptidyl aminopeptidase-like protein 6 showed a specific down-regulation in AD. However, no differences were observed in the olfactory expression of this protein panel in PSP subjects. This study demonstrates an olfactory progressive proteome modulation in AD, unveiling cross-disease similarities and differences especially for specific proteins involved in dendritic and axonic distributions that occur in the OB during the neurodegenerative process.

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