ABSTRACT
INTRODUCTION: Bexarotene, a retinoid X receptor agonist, improves cognition in murine models of Alzheimer's disease (AD). This study evaluated the effects of bexarotene on pathological and electrophysiological changes in very old triple transgenic AD mice (3xTg-AD mice). METHODS: 24-month-old 3xTg-AD mice were treated with bexarotene (100 mg/kg/day for 30 days). The Morris water maze was used to evaluate spatial memory; immunofluorescence and confocal microscopy were used to evaluate pathological changes; and in vivo electrophysiological recordings were used to evaluate basal transmission and plasticity in the commissural CA3-CA1 pathway. RESULTS: In addition to cognitive improvement, bexarotene-treated 3xTg-AD mice were found to have 1) reductions of astrogliosis and reactive microglia both in cortex and hippocampus; 2) increased ApoE expression restricted to CA1; 3) increased number of cells co-labeled with ApoE and NeuN; 4) recovery of NeuN expression, suggesting neuronal protection; and, 5) recovery of basal synaptic transmission and synaptic plasticity. DISCUSSION: These results indicate that bexarotene-induced improvement in cognition is due to multiple changes that contribute to recovery of synaptic plasticity.
Subject(s)
Alzheimer Disease/drug therapy , Bexarotene/therapeutic use , Hippocampus/drug effects , Neuroprotective Agents/therapeutic use , Alzheimer Disease/genetics , Animals , Apolipoproteins E/metabolism , Bexarotene/pharmacology , DNA-Binding Proteins/metabolism , Female , Gliosis , Hippocampus/growth & development , Hippocampus/metabolism , Hippocampus/physiopathology , Male , Maze Learning , Mice , Nerve Tissue Proteins/metabolism , Neuroglia/metabolism , Neuronal Plasticity , Neuroprotective Agents/pharmacology , Synaptic TransmissionABSTRACT
OBJECTIVE: To study DNA methylation patterns of cortical pyramidal layers susceptible to late-onset Alzheimer's disease (LOAD) neurodegeneration. METHODS: Laser-assisted microdissection to select pyramidal layers' cells in frontal cortex of 32 human brains (18 LOAD) and Infinium DNA Methylation 450K analysis were performed to find differential methylated positions and regions, in addition to the corresponding gene set functional enrichment analyses. RESULTS: Differential hypermethylation in several genomic regions and genes mainly in HOXA3, GSTP1, CXXC1-3 and BIN1. The functional enrichment analysis revealed genes significantly related to oxidative-stress and synapsis. CONCLUSION: The present results indicate the differentially methylated genes related to neural projections, synapsis, oxidative stress and epigenetic regulator genes and represent the first epigenome of cortical pyramidal layers in LOAD.