title: Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer's mouse model by controlling β-amyloid production.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38α to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38α signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptoms with the downregulation of p38α only in neurons (5XFAD/p38α∆-N). We found that the neuronal-specific deletion of p38α improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38α∆-N mice display reduced amyloid-β accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38α signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-β deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Colié
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona - CSIC and Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Sarroca
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", CSIC - Universidad Autónoma de Madrid, 28049 Madrid, Spain.|School of Biosciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Palenzuela
authors.affiliation: Cellular Oncology Group, Biodonostia Institute, 20014 San Sebastian and Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: Garcia
authors.affiliation: Cellular Oncology Group, Biodonostia Institute, 20014 San Sebastian and Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Matheu
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona - CSIC and Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Corpas
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", CSIC - Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Dotti
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", CSIC - Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Esteban
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona - CSIC and Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
authors.forename: Coral
authors.initials: C
authors.lastname: Sanfeliu
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.|ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D060825:Cognitive Dysfunction / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000172:deficiency / Q000235:genetics*; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D048308:Mitogen-Activated Protein Kinase 14