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J Mol Neurosci ; 58(2): 243-53, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26553261

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.


Subject(s)
Alzheimer Disease/metabolism , Benzoates/pharmacology , Benzylamines/pharmacology , DNA Methylation/drug effects , Neurogenesis , Orphan Nuclear Receptors/agonists , Synapses/drug effects , Alzheimer Disease/genetics , Animals , Female , HMGB3 Protein/genetics , HMGB3 Protein/metabolism , Liver X Receptors , Mice , Qa-SNARE Proteins/genetics , Qa-SNARE Proteins/metabolism , Retinoblastoma-Binding Protein 7/genetics , Retinoblastoma-Binding Protein 7/metabolism , Synapses/metabolism , Synaptophysin/genetics , Synaptophysin/metabolism
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