Journal of Molecular Neuroscience

, Volume 58, Issue 2, pp 243–253 | Cite as

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

  • A. G. Sandoval-Hernández
  • H. G. Hernández
  • A. Restrepo
  • J. I. Muñoz
  • G. F. Bayon
  • A. F. Fernández
  • M. F. Fraga
  • G. P. Cardona-Gómez
  • H. Arboleda
  • Gonzalo H. Arboleda
Article
First Online:
Received:
Accepted:

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.

Keywords

Alzheimer’s disease Liver X receptors Triple transgenic mice GW3965 
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Notes

Acknowledgments

We thank Dr. Jon Collins (GlaxoSmithKline, Stevenage, UK) for providing GW683965A. This study was funded by Colciencias (Contract Nos. 401-2011 and 498-2012).

Compliance with Ethical Standards

Animals were handled following the Colombian (Law 84 of 1989 and Resolution 8430 of 1993) and international regulations and standards on animal welfare and conformed to the Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines (Kilkenny et al. 2010).

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12031_2015_665_MOESM1_ESM.xlsx (16 kb)
Table S1 Differentially methylated Illumina probes of 3xTg-AD group treated with LXR agonist in comparison with DMSO-treated 3xTg-AD group (XLSX 16 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • A. G. Sandoval-Hernández
    • 1
  • H. G. Hernández
    • 4
  • A. Restrepo
    • 1
  • J. I. Muñoz
    • 2
  • G. F. Bayon
    • 3
  • A. F. Fernández
    • 3
  • M. F. Fraga
    • 3
  • G. P. Cardona-Gómez
    • 2
  • H. Arboleda
    • 4
  • Gonzalo H. Arboleda
    • 1
    • 5
  1. 1.Grupo de Muerte Celular, Instituto de GenéticaUniversidad Nacional de ColombiaBogotáColombia
  2. 2.Área de Neurobiología Celular y Molecular, Grupo de Neurociencias de AntioquiaUniversidad de AntioquiaMedellínColombia
  3. 3.Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), Hospital Universitario Central de Asturias (HUCA)Universidad de OviedoOviedoSpain
  4. 4.Grupo de NeurocienciasUniversidad NacionalBogotáColombia
  5. 5.Departamento de Patología, Facultad de MedicinaUniversidad Nacional de ColombiaBogotáColombia

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