title: Impaired Src signaling and post-synaptic actin polymerization in Alzheimer's disease mice hippocampus--linking NMDA receptors and the reelin pathway.
abstract: Early cognitive deficits in Alzheimer's disease (AD) have been related to deregulation of N-methyl-d-aspartate receptors (NMDARs) and synaptic dysfunction in response to amyloid-beta peptide. NMDAR anchorage to post-synaptic membrane depends in part on Src kinase, which is also implicated in NMDAR activation and actin cytoskeleton stabilization, two processes relevant for normal synaptic function. In this study we analyzed the changes in GluN2B subunit phosphorylation and the levels of proteins involved in Src related signaling pathways linking the Tyr kinase to actin cytoskeleton polymerization, namely reelin, disabled-1 (Dab1) and cortactin, in hippocampal and cortical homogenates obtained from the triple transgenic mouse model of AD (3xTg-AD) that shows progression of pathology as a function of age versus age-matched wild-type mice. Moreover, we evaluated regional post-synaptic actin polymerization using phalloidin labeling in hippocampal slices. Young (3month-old) 3xTg-AD male mice hippocampus exhibited decreased GluN2B Tyr1472 phosphorylation and reduced Src activity. In the cortex, decreased Src activity correlated with reduced levels of reelin and Dab1, implicating changes in the reelin pathway. We also observed diminished phosphorylated Dab1 and cortactin protein levels in the hippocampus and cortex of young 3xTg-AD male mice. Concordantly with the recognized role of these proteins in actin stabilization, we detected a significant decrease in post-synaptic F-actin in 3month-old 3xTg-AD male CA1 and CA3 hippocampal regions. These data suggest deregulated Src-dependent signaling pathways involving GluN2B-composed NMDARs and post-synaptic actin cytoskeleton depolymerization in the hippocampus in early stages of AD.
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal. Electronic address: sandraisab.mota@gmail.com.
authors.forename: Sandra I
authors.initials: SI
authors.lastname: Mota
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal. Electronic address: ildetelferreira@gmail.com.
authors.forename: Ildete L
authors.initials: IL
authors.lastname: Ferreira
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal. Electronic address: jorge.valero@cnc.uc.pt.
authors.forename: Jorge
authors.initials: J
authors.lastname: Valero
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal. Electronic address: beferreiro@gmail.com.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Ferreiro
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal; Life Science Department, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal. Electronic address: alc@cnc.uc.pt.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Carvalho
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address: catarina.n.oliveira@gmail.com.
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Oliveira
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address: acrego@cnc.uc.pt.
authors.forename: A Cristina
authors.initials: AC
authors.lastname: Rego
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D012737:Sex Factors; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics
chemical_list: D000199:Actins; D016564:Amyloid beta-Protein Precursor; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; D016875:tau Proteins; D019061:src-Family Kinases; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases
keywords: 3xTg-AD mice; Alzheimer's disease; Cortactin; Dab1; F-actin; GluN2B subunits; Reelin; Src kinase