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. 2018 Jan:86:1-15.
doi: 10.1016/j.mcn.2017.11.002. Epub 2017 Nov 4.

Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer's disease

Roy Lardenoije  1 , Daniël L A van den Hove  2 , Monique Havermans  3 , Anne van Casteren  3 , Kevin X Le  4 , Roberta Palmour  5 , Cynthia A Lemere  4 , Bart P F Rutten  6
Affiliations

Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer's disease

Roy Lardenoije et al. Mol Cell Neurosci. 2018 Jan.

Abstract

Both aging and Alzheimer's disease (AD) are associated with widespread epigenetic changes, with most evidence suggesting global hypomethylation in AD. It is, however, unclear how these age-related epigenetic changes are linked to molecular aberrations as expressed in animal models of AD. Here, we investigated age-related changes of epigenetic markers of DNA methylation and hydroxymethylation in a range of animal models of AD, and their correlations with amyloid plaque load. Three transgenic mouse models, including the J20, APP/PS1dE9 and 3xTg-AD models, as well as Caribbean vervets (a non-transgenic non-human primate model of AD) were investigated. In the J20 mouse model, an age-related decrease in DNA methylation was found in the dentate gyrus (DG) and a decrease in the ratio between DNA methylation and hydroxymethylation was found in the DG and cornu ammonis (CA) 3. In the 3xTg-AD mice, an age-related increase in DNA methylation was found in the DG and CA1-2. No significant age-related alterations were found in the APP/PS1dE9 mice and non-human primate model. In the J20 model, hippocampal plaque load showed a significant negative correlation with DNA methylation in the DG, and with the ratio a negative correlation in the DG and CA3. For the APP/PS1dE9 model a negative correlation between the ratio and plaque load was observed in the CA3, as well as a negative correlation between DNA methyltransferase 3A (DNMT3A) levels and plaque load in the DG and CA3. Thus, only the J20 model showed an age-related reduction in global DNA methylation, while DNA hypermethylation was observed in the 3xTg-AD model. Given these differences between animal models, future studies are needed to further elucidate the contribution of different AD-related genetic variation to age-related epigenetic changes.

Keywords: Aging; Alzheimer's disease; Animal models; DNA hydroxymethylation; DNA methylation; DNA methyltransferase; Hippocampus.

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Figures

Figure 1.
Figure 1.
Semi-quantitative analysis results of age-related alterations in 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and DNA methyltransferase 3A (DNMT3A) immunoreactivity (IR), and the 5mC:5hmC ratio in J20 mice. Shown are the background-corrected and scaled integrated density data plotted against the age of the animals, the fitted linear regression lines and the standard error (SE) of the regression lines, for the dentate gyrus (DG), cornu ammonis (CA) 3, and CA1–2 subregions of the hippocampus. A statistically significant effect of age on 5mC IR was found in the DG (p = 0.037), and on the 5mC:5hmC ratio in the DG (p = 0.018) and CA3 (p = 0.038). AU, arbitrary units.
Figure 2.
Figure 2.
Semi-quantitative analysis results of age-related alterations in 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and DNA methyltransferase 3A (DNMT3A) immunoreactivity (IR), and the 5mC:5hmC ratio in APP/PS1dE9 mice. Shown are the background-corrected and scaled integrated density data plotted against the age of the animals, the fitted linear regression lines and the standard error (SE) of the regression lines, for the dentate gyrus (DG), cornu ammonis (CA) 3, and CA1–2 subregions of the hippocampus. No statistically significant effect of age on any of the investigated epigenetic markers was found. AU, arbitrary units.
Figure 3.
Figure 3.
Semi-quantitative analysis results of age-related alterations in 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and DNA methyltransferase 3A (DNMT3A) immunoreactivity (IR), and the 5mC:5hmC ratio in 3xTg-AD mice. Shown are the background-corrected and scaled integrated density data plotted against the age of the animals, the fitted linear regression lines and the standard error (SE) of the regression lines, for the dentate gyrus (DG), cornu ammonis (CA) 3, and CA1–2 subregions of the hippocampus. A statistically significant effect of age on 5mC IR was found in the DG (p = 0.022) and CA1–2 (p = 0.037). AU, arbitrary units.
Figure 4.
Figure 4.
Semi-quantitative analysis results of age-related alterations in 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and DNA methyltransferase 3A (DNMT3A) immunoreactivity (IR), and the 5mC:5hmC ratio in Caribbean vervets. Shown are the background-corrected and scaled integrated density data plotted against the age of the animals, the fitted linear regression lines and the standard error (SE) of the regression lines, for the dentate gyrus (DG), cornu ammonis (CA) 3, and CA1–2 subregions of the hippocampus. No statistically significant effect of age on any of the investigated epigenetic markers was found. AU, arbitrary units.
Figure 5.
Figure 5.
Correlation analysis results between epigenetic markers 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and DNA methyltransferase 3A (DNMT3A) immunoreactivity (IR), and the 5mC:5hmC ratio, and plaque load in J20 mice. Shown are the background-corrected and scaled integrated density data plotted against the scaled fraction of hippocampal area covered by plaques, for the dentate gyrus (DG), cornu ammonis (CA) 3, and CA1–2 subregions of the hippocampus. Fitted linear regression lines are shown for clarity. A statistically significant correlation with plaque load was found for 5mC IR in the DG (tau = −0.49, p = 0.034), and the 5mC:5hmC ratio in the DG (tau = −0.52, p = 0.024) and CA3 (tau = −0.46, p = 0.047). AU, arbitrary units.
Figure 6.
Figure 6.
Correlation analysis results between epigenetic markers 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and DNA methyltransferase 3A (DNMT3A) immunoreactivity (IR), and the 5mC:5hmC ratio, and plaque load in APP/PS1dE9 mice. Shown are the background-corrected and scaled integrated density data plotted against the scaled fraction of hippocampal area covered by plaques, for the dentate gyrus (DG), cornu ammonis (CA) 3, and CA1–2 subregions of the hippocampus. Fitted linear regression lines are shown for clarity. A statistically significant correlation with plaque load was found for the 5mC:5hmC ratio in the CA3 (tau = −0.71, p = 0.019), and DNMT3A IR in the DG (tau = −0.56, p = 0.048) and CA3 (tau = −0.61, p = 0.029). AU, arbitrary units.
Figure 7.
Figure 7.
Correlation analysis results between epigenetic markers 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and DNA methyltransferase 3A (DNMT3A) immunoreactivity (IR), and the 5mC:5hmC ratio, and plaque load in 3xTg-AD mice. Shown are the background-corrected and scaled integrated density data plotted against the scaled fraction of hippocampal area covered by plaques, for the dentate gyrus (DG), cornu ammonis (CA) 3, and CA1–2 subregions of the hippocampus. Fitted linear regression lines are shown for clarity. No statistically significant correlation was found between plaque load and any of the investigated epigenetic markers. AU, arbitrary units.
Figure 8.
Figure 8.
Correlation analysis results between epigenetic markers 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and DNA methyltransferase 3A (DNMT3A) immunoreactivity (IR), and the 5mC:5hmC ratio, and plaque load in Caribbean vervets. Shown are the backgroundcorrected and scaled integrated density data plotted against the scores of hippocampal plaque load, for the dentate gyrus (DG), cornu ammonis (CA) 3, and CA1–2 subregions of the hippocampus. Fitted linear regression lines are shown for clarity. No statistically significant correlation was found between plaque load and any of the investigated epigenetic markers. AU, arbitrary units.
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