title: Evidence for an imbalance between tau O-GlcNAcylation and phosphorylation in the hippocampus of a mouse model of Alzheimer's disease.
abstract: Intracellular accumulation of hyperphosphorylated tau protein is linked to neuronal degeneration in Alzheimer's disease (AD). Mounting evidence suggests that tau phosphorylation and O-N-acetylglucosamine glycosylation (O-GlcNAcylation) are mutually exclusive post-translational modifications. O-GlcNAcylation depends on 3-5% of intracellular glucose that enters the hexosamine biosynthetic pathway. To our knowledge, the existence of an imbalance between tau phosphorylation and O-GlcNAcylation has not been reported in animal models of AD, as yet. Here, we used triple transgenic (3xTg-AD) mice at 12 months, an age at which hyperphosphorylated tau is already detected and associated with cognitive decline. In these mice, we showed that tau was hyperphosphorylated on both Ser396 and Thr205 in the hippocampus, and to a lower extent and exclusively on Thr205 in the frontal cortex. Tau O-GlcNAcylation, assessed in tau immunoprecipitates, was substantially reduced in the hippocampus of 3xTg-AD mice, with no changes in the frontal cortex or in the cerebellum. No changes in the expression of the three major enzymes involved in O-GlcNAcylation, i.e., glutamine fructose-6-phosphate amidotransferase, O-linked β-N-acetylglucosamine transferase, and O-GlcNAc hydrolase were found in the hippocampus of 3xTg-AD mice. These data demonstrate that an imbalance between tau phosphorylation and O-GlcNAcylation exists in AD mice, and strengthens the hypothesis that O-GlcNAcylation might be targeted by disease modifying drugs in AD.
authors.affiliation: Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France; LIA France/Italy, International Associated Laboratory "Prenatal Stress and Neurodegenerative Diseases", Glycobiology of Stress-Related Diseases Team, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France; Neuromed, 86077 Pozzilli, Italy; Sapienza University of Rome, 00185 Rome, Italy. Electronic address: eleogatta@gmail.com.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gatta
authors.affiliation: Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France. Electronic address: tony.lefebvre@univ-lille1.fr.
authors.forename: Tony
authors.initials: T
authors.lastname: Lefebvre
authors.affiliation: Dept. of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy. Electronic address: silvana.gaetani@uniroma1.it.
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaetani
authors.affiliation: INSERM, UMR-S 1130, Neuroscience Paris Seine, 75005 Paris, France. Electronic address: marc.dos_santos@etu.upmc.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: dos Santos
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, 10065 New York, NY, USA; LIA France/Italy, International Associated Laboratory "Prenatal Stress and Neurodegenerative Diseases", Glycobiology of Stress-Related Diseases Team, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France; Neuromed, 86077 Pozzilli, Italy; Sapienza University of Rome, 00185 Rome, Italy. Electronic address: jmarrocco@mail.rockefeller.edu.
authors.forename: Jordan
authors.initials: J
authors.lastname: Marrocco
authors.affiliation: Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mir
authors.affiliation: Dept. of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy. Electronic address: tommaso.cassano@unifg.it.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cassano
authors.affiliation: Univ. Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France; LIA France/Italy, International Associated Laboratory "Prenatal Stress and Neurodegenerative Diseases", Glycobiology of Stress-Related Diseases Team, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France; Neuromed, 86077 Pozzilli, Italy; Sapienza University of Rome, 00185 Rome, Italy. Electronic address: stefania.maccari@univ-lille1.fr.
authors.forename: Stefania
authors.initials: S
authors.lastname: Maccari
authors.affiliation: Dept. of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy; IRCCS Neuromed, 86077 Pozzilli, Italy. Electronic address: ferdinandonicoletti@hotmail.com.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Robert Debré Children Hospital INSERM U1141, 75019, France. Electronic address: j_mairesse@hotmail.com.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Mairesse
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000215:Acylation; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006031:Glycosylation; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D000117:Acetylglucosamine
keywords: 3xTg-AD mice; O-GlcNAcylation; hippocampus; tau protein