title: An early dysregulation of FAK and MEK/ERK signaling pathways precedes the β-amyloid deposition in the olfactory bulb of APP/PS1 mouse model of Alzheimer's disease.
abstract: Olfactory dysfunction is an early event of Alzheimer's disease (AD). However, the mechanisms associated to AD neurodegeneration in olfactory areas are unknown. Here we used double-transgenic amyloid precursor protein/presenilin 1 (APPswe/PS1dE9) mice and label-free quantitative proteomics to analyze early pathological effects on the olfactory bulb (OB) during AD progression. Prior to β-amyloid plaque formation, 9 modulated proteins were detected on 3-month-old APP/PS1 mice while 16 differential expressed proteins were detected at 6months, when β-amyloid plaques appear, indicating a moderate imbalance in cytoskeletal rearrangement, and synaptic plasticity in APP/PS1 OBs. Moreover, β-amyloid induced an inactivation of focal adhesion kinase (FAK) together with a transient activation of MEK1/2, leading to inactivation of ERK1/2 in 6-months APP/PS1 OBs. In contrast, the analysis of human OBs revealed a late activation of FAK in advanced AD stages, whereas ERK1/2 activation was enhanced across AD staging respect to controls. This survival potential was accompanied by the inhibition of the proapototic factor BAD in the OB across AD phenotypes. Our data contribute to a better understanding of the early molecular mechanisms that are modulated in AD neurodegeneration, highlighting significant differences in the regulation of survival pathways between APP/PS1 mice and sporadic human AD.
  
  
  
  Loss of smell is involved in early stages of Alzheimer's disease (AD), usually preceding classic disease symptoms. However, the mechanisms governing this dysfunction are still poorly understood, losing its potential as a useful tool for clinical diagnosis. Our study characterizes potential AD-associated molecular changes in APP/PS1 mice olfactory bulb (OB) using MS-quantitative proteomics, revealing early cytoskeletal disruption and synaptic plasticity impairment. Moreover, an opposite pattern was found when comparing the activation status of specific survival pathways between APP/PS1 OBs and OBs derived from sAD subjects with different neuropathological grading. Our data reflect, in part, the progressive effect of APP overproduction and Aβ accumulation on the OB proteome during AD progression.
authors: Clinical Neuroproteomics Group, Navarrabiomed Biomedical Research Center, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Mercedes
authors: M
authors: Lachén-Montes
authors: Clinical Neuroproteomics Group, Navarrabiomed Biomedical Research Center, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Andrea
authors: A
authors: González-Morales
authors: Proteomics Unit, Navarrabiomed Biomedical Research Center, Proteored-ISCIII, Instituto de investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Xabier Martínez
authors: XM
authors: de Morentin
authors: Proteomics Unit, Navarrabiomed Biomedical Research Center, Proteored-ISCIII, Instituto de investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Estela
authors: E
authors: Pérez-Valderrama
authors: Proteomics Unit, Navarrabiomed Biomedical Research Center, Proteored-ISCIII, Instituto de investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Karina
authors: K
authors: Ausín
authors: Clinical Neuroproteomics Group, Navarrabiomed Biomedical Research Center, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: María Victoria
authors: MV
authors: Zelaya
authors: Sciex., Valgrande 8, Edificio Thanworth II, Alcobendas, Madrid, Spain.
authors: Antonio
authors: A
authors: Serna
authors: Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Spain.
authors: Ester
authors: E
authors: Aso
authors: Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Spain.
authors: Isidro
authors: I
authors: Ferrer
authors: Clinical Neuroproteomics Group, Navarrabiomed Biomedical Research Center, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Proteomics Unit, Navarrabiomed Biomedical Research Center, Proteored-ISCIII, Instituto de investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors: Joaquín
authors: J
authors: Fernández-Irigoyen
authors: Clinical Neuroproteomics Group, Navarrabiomed Biomedical Research Center, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Proteomics Unit, Navarrabiomed Biomedical Research Center, Proteored-ISCIII, Instituto de investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. Electronic address: esantamma@navarra.es.
authors: Enrique
authors: E
authors: Santamaría
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D018450:Disease Progression; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D000857:Olfaction Disorders / Q000209:etiology*; D009830:Olfactory Bulb / Q000378:metabolism / Q000473:pathology*; D058225:Plaque, Amyloid
chemical_list: D016229:Amyloid beta-Peptides; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: APP/PS1 model; Alzheimer; Brain; Olfactory bulb; Proteomics