title: Liver X Receptor Agonist Modifies the DNA Methylation Profile of Synapse and Neurogenesis-Related Genes in the Triple Transgenic Mouse Model of Alzheimer's Disease.
abstract: The liver X receptor agonist, GW3965, improves cognition in Alzheimer's disease (AD) mouse models. Here, we determined if short-term GW3965 treatment induces changes in the DNA methylation state of the hippocampus, which are associated with cognitive improvement. Twenty-four-month-old triple-transgenic AD (3xTg-AD) mice were treated with GW3965 (50 mg/kg/day for 6 days). DNA methylation state was examined by modified bisulfite conversion and hybridization on Illumina Infinium Methylation BeadChip 450 k arrays. The Morris water maze was used for behavioral analysis. Our results show in addition to improvement in cognition methylation changes in 39 of 13,715 interrogated probes in treated 3xTg-AD mice compared with untreated 3xTg-AD mice. These changes in methylation probes include 29 gene loci. Importantly, changes in methylation status were mainly from synapse-related genes (SYP, SYN1, and DLG3) and neurogenesis-associated genes (HMGB3 and RBBP7). Thus, our results indicate that liver X receptors (LXR) agonist treatment induces rapid changes in DNA methylation, particularly in loci associated with genes involved in neurogenesis and synaptic function. Our results suggest a new potential mechanism to explain the beneficial effect of GW3965.
authors.affiliation: Grupo de Muerte Celular, Instituto de Genética, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: A G
authors.initials: AG
authors.lastname: Sandoval-Hernández
authors.affiliation: Grupo de Neurociencias, Universidad Nacional, Bogotá, Colombia.
authors.forename: H G
authors.initials: HG
authors.lastname: Hernández
authors.affiliation: Grupo de Muerte Celular, Instituto de Genética, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: A
authors.initials: A
authors.lastname: Restrepo
authors.affiliation: Área de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
authors.forename: J I
authors.initials: JI
authors.lastname: Muñoz
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: G F
authors.initials: GF
authors.lastname: Bayon
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: A F
authors.initials: AF
authors.lastname: Fernández
authors.affiliation: Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Fraga
authors.affiliation: Área de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
authors.forename: G P
authors.initials: GP
authors.lastname: Cardona-Gómez
authors.affiliation: Grupo de Neurociencias, Universidad Nacional, Bogotá, Colombia.
authors.forename: H
authors.initials: H
authors.lastname: Arboleda
authors.affiliation: Grupo de Muerte Celular, Instituto de Genética, Universidad Nacional de Colombia, Bogotá, Colombia. gharboledab@unal.edu.co.|Departamento de Patología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia. gharboledab@unal.edu.co.
authors.forename: Gonzalo H
authors.initials: GH
authors.lastname: Arboleda
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects*; D005260:Female; D025765:HMGB3 Protein / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D055495:Neurogenesis; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D056524:Retinoblastoma-Binding Protein 7 / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism
chemical_list: D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D025765:HMGB3 Protein; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D050765:Qa-SNARE Proteins; C096378:Rbbp7 protein, mouse; D056524:Retinoblastoma-Binding Protein 7; D016708:Synaptophysin; C569015:Syp protein, mouse
keywords: Alzheimer’s disease; GW3965; Liver X receptors; Triple transgenic mice