title: Rescue of impaired late-phase long-term depression in a tau transgenic mouse model.
abstract: Cognitive decline, the hallmark of Alzheimer's disease, and accompanying neuropsychiatric symptoms share dysfunctions of synaptic processes as a common cellular pathomechanism. Long-term potentiation has proven to be a sensitive tool for the "diagnosis" of such synaptic dysfunctions. Much less, however, is known about how long-term depression (LTD), an alternative mechanism for the storage of memory, is affected by Alzheimer's disease progression. Here, we demonstrate that impaired late LTD (>3 hours) in THY-Tau22 mice can be rescued by either inhibition of glycogen synthase kinase-3 (GSK3β) activity or by application of the protein-phosphatase 2A agonist selenate. In line with these findings, we observed increased phosphorylation of GSK3β at Y216 and reduced total phosphatase activity in biochemical assays of hippocampal tissue of THY-Tau22 mice. Interestingly, LTD induction and pharmacologic inhibition of GSK3β appeared to downregulate GSK3ß activity via a marked upregulation of phosphorylation at the inhibitory Ser9 residue. Our results point to alterations in phosphorylation and/or dephosphorylation homeostasis as key mechanisms underlying the deficits in LTD and hippocampus-dependent learning found in THY-Tau22 mice.
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Leuven, Belgium.
authors.forename: Tariq
authors.initials: T
authors.lastname: Ahmed
authors.affiliation: Université Lille-Nord de France, UDSL, Lille, France; Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France; CHRU-Lille, Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Blum
authors.affiliation: Université Lille-Nord de France, UDSL, Lille, France; Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France; Max-Planck Institute for Biology of Ageing, Köln, Germany.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Burnouf
authors.affiliation: Université Lille-Nord de France, UDSL, Lille, France; Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Demeyer
authors.affiliation: Université Lille-Nord de France, UDSL, Lille, France; Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France; CHRU-Lille, Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Buée-Scherrer
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Université Lille-Nord de France, UDSL, Lille, France; Inserm UMR837, Jean-Pierre Aubert Research Centre, Lille, France; CHRU-Lille, Lille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: Laboratory of Biological Psychology, University of Leuven, Leuven, Belgium. Electronic address: Detlef.Balschun@ppw.kuleuven.be.
authors.forename: Detlef
authors.initials: D
authors.lastname: Balschun
mesh_terms: D000544:Alzheimer Disease / Q000523:psychology; D000818:Animals; D003863:Depression / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000523:psychology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D007858:Learning; D017774:Long-Term Potentiation; D008297:Male; D008568:Memory; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics*
chemical_list: D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2
keywords: Alzheimer's disease; CA1-region; Glycogen synthase kinase-3; Hippocampus; LTD; Long-term depression; Okadaic acid; Protein-phosphatase 2A; SB216763; Sodium selenate; Synaptic plasticity; Tauopathy