title: Olfactory bulb proteome dynamics during the progression of sporadic Alzheimer's disease: identification of common and distinct olfactory targets across Alzheimer-related co-pathologies.
abstract: 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.
authors.affiliation: Proteomics Unit, Clinical Neuroproteomics Group, Navarrabiomed, Fundación Miguel Servet, Proteored-ISCIII, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Zelaya
authors.affiliation: Proteomics Unit, Clinical Neuroproteomics Group, Navarrabiomed, Fundación Miguel Servet, Proteored-ISCIII, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Pérez-Valderrama
authors.affiliation: Proteomics Unit, Clinical Neuroproteomics Group, Navarrabiomed, Fundación Miguel Servet, Proteored-ISCIII, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: Xabier Martínez
authors.initials: XM
authors.lastname: de Morentin
authors.affiliation: Pathological Anatomy Department, Navarra Hospital Complex, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Tuñon
authors.affiliation: Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.|CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Madrid, Spain.
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: 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.
authors.forename: María Rosario
authors.initials: MR
authors.lastname: Luquin
authors.affiliation: Proteomics Unit, Clinical Neuroproteomics Group, Navarrabiomed, Fundación Miguel Servet, Proteored-ISCIII, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Fernandez-Irigoyen
authors.affiliation: Proteomics Unit, Clinical Neuroproteomics Group, Navarrabiomed, Fundación Miguel Servet, Proteored-ISCIII, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Santamaría
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001344:Autopsy; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D009830:Olfactory Bulb / Q000378:metabolism*; D060066:Protein Interaction Maps; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D013494:Supranuclear Palsy, Progressive / Q000378:metabolism / Q000473:pathology
chemical_list: D020543:Proteome
keywords: Alzheimer; Gerotarget; neurodegeneration; olfactory bulb; proteomics