title: PTEN recruitment controls synaptic and cognitive function in Alzheimer's models.
abstract: Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.|Unidad de Biofísica CSIC-UPV/EHU, Campus Universidad del País Vasco, Leioa, Spain.|Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Shira
authors.initials: S
authors.lastname: Knafo
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Puelles
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Ernest
authors.initials: E
authors.lastname: Palomer
authors.affiliation: Unidad de Biofísica CSIC-UPV/EHU, Campus Universidad del País Vasco, Leioa, Spain.
authors.forename: Igotz
authors.initials: I
authors.lastname: Delgado
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Draffin
authors.affiliation: Biocruces Health Research Institute, Barakaldo, Spain.
authors.forename: Janire
authors.initials: J
authors.lastname: Mingo
authors.affiliation: VIB Center for the Biology of Disease and Center for Human Genetics, University of Leuven (Katholieke University of Leuven), Leuven, Belgium.|IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Wahle
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Kanwardeep
authors.initials: K
authors.lastname: Kaleka
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Mou
authors.affiliation: Department of Psychobiology, Universidad Nacional de Educación a Distancia, Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Pereda-Perez
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, and Norris Cotton Cancer Center, Lebanon, New Hampshire, USA.
authors.forename: Edvin
authors.initials: E
authors.lastname: Klosi
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, and Norris Cotton Cancer Center, Lebanon, New Hampshire, USA.
authors.forename: Erik B
authors.initials: EB
authors.lastname: Faber
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, and Norris Cotton Cancer Center, Lebanon, New Hampshire, USA.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Chapman
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Lozano-Montes
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ortega-Molina
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED).
authors.forename: Lara
authors.initials: L
authors.lastname: Ordóñez-Gutiérrez
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED).
authors.forename: Francisco
authors.initials: F
authors.lastname: Wandosell
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Viña
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Dotti
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Randy A
authors.initials: RA
authors.lastname: Hall
authors.affiliation: Ikerbasque, Basque Foundation for Science, Bilbao, Spain.|Biocruces Health Research Institute, Barakaldo, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Pulido
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Nashaat Z
authors.initials: NZ
authors.lastname: Gerges
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Chan
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, and Norris Cotton Cancer Center, Lebanon, New Hampshire, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Spaller
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.affiliation: Department of Psychobiology, Universidad Nacional de Educación a Distancia, Madrid, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Venero
authors.affiliation: Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: José A
authors.identifier: http://orcid.org/0000-0002-3759-3300
authors.initials: JA
authors.lastname: Esteban
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D003072:Cognition Disorders / Q000150:complications / Q000503:physiopathology*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D051379:Mice; D008822:Mice, Transgenic; D054731:PDZ Domains / Q000235:genetics / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D061251:Primary Cell Culture; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D051059:PTEN Phosphohydrolase