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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

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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.

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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).

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Authors and Affiliations

  1. Grupo de Muerte Celular, Instituto de Genética, Universidad Nacional de Colombia, Bogotá, Colombia

    A. G. Sandoval-Hernández, A. Restrepo & Gonzalo H. Arboleda

  2. Área de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia

    J. I. Muñoz & G. P. Cardona-Gómez

  3. Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), Hospital Universitario Central de Asturias (HUCA), Universidad de Oviedo, Oviedo, Spain

    G. F. Bayon, A. F. Fernández & M. F. Fraga

  4. Grupo de Neurociencias, Universidad Nacional, Bogotá, Colombia

    H. G. Hernández & H. Arboleda

  5. Departamento de Patología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia

    Gonzalo H. Arboleda

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  1. A. G. Sandoval-Hernández
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Correspondence to Gonzalo H. Arboleda.

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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).

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The authors declare that they have no competing interests.

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A. G. Sandoval-Hernández and H. G. Hernández contributed equally to this work.

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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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Sandoval-Hernández, A.G., Hernández, H.G., Restrepo, A. et al. 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. J Mol Neurosci 58, 243–253 (2016). https://doi.org/10.1007/s12031-015-0665-8

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