title: γ-Hydroxybutyrate (Xyrem) ameliorates clinical symptoms and neuropathology in a mouse model of Alzheimer's disease.
abstract: The chronic decrease of brain amyloid-β (Aβ) peptides is an emerging therapeutic for Alzheimer's disease, but no such treatment has achieved clinical validation yet. In vivo, some brain proteases, including neprilysin, possess the ability of degrading Aβ and experimental data suggest their exploitation in strategies to reduce cerebral Aβ concentration. Previous studies have shown that pharmacologic doses of gamma-hydroxybutyrate (sodium oxybate or Xyrem) induce histone deacetylases (HDACs) inhibition and neprilysin gene expression. Here, we demonstrate that brain neprilysin overexpression induced in vivo by repeated gamma-hydroxybutyrate autoadministration reduces cerebral Aβ contents and prevents cognitive deficits in APPSWE mice. Oral gamma-hydroxybutyrate also counteracted phosphoramidon-induced brain neprilysin inhibition and Aβ accumulation. HDACs activities in SH-SY5Y cells were inhibited by gamma-hydroxybutyrate which did not affect amyloid peptide precursor intracellular domain. Together, our results suggest that gamma-hydroxybutyrate, acting via HDAC inhibition, upregulates neprilysin to reduce Aβ level and related memory deficits. Because gamma-hydroxybutyrate doses used herein are clinically relevant, our data suggest that chronic oral administration of gamma-hydroxybutyrate or its analogs may be considered for strategies against presymptomatic or established Alzheimer's disease.
authors.affiliation: Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, Strasbourg, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, Centre National de la Recherche Scientifique, Université de Strasbourg, UMR 7237, Strasbourg, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathis
authors.affiliation: Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, Strasbourg, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Leva
authors.affiliation: Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, Strasbourg, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Patte-Mensah
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, Centre National de la Recherche Scientifique, Université de Strasbourg, UMR 7237, Strasbourg, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Cassel
authors.affiliation: Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, Strasbourg, France. Electronic address: maitre@unistra.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Maitre
authors.affiliation: Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, Strasbourg, France.
authors.forename: Ayikoe G
authors.initials: AG
authors.lastname: Mensah-Nyagan
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D012978:Sodium Oxybate / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D056572:Histone Deacetylase Inhibitors; D012978:Sodium Oxybate; D015260:Neprilysin; D006655:Histone Deacetylases
keywords: Alzheimer's disease; Aβ peptides; Neprilysin; Xyrem; γ−Hydroxybutyrate