期刊
MOLECULAR AND CELLULAR NEUROSCIENCE
卷 86, 期 -, 页码 1-15出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2017.11.002
关键词
Alzheimer's disease; Aging; Hippocampus; DNA methylation; DNA hydroxymethylation; DNA methyltransferase; Animal models
资金
- Internationale Stichting Alzheimer Onderzoek (ISAO) [07551, 11532]
- ISAO [09552, 13515]
- Netherlands Organization for Scientific Research (NWO) [916.11.086]
- ISAO fellowship, NWO [022.005.019]
- Anonymous Foundation
- NIH/NIA [R01 AG040092]
- Joint Programme Neurodegenerative Disease Research (JPND)
- JPND
- Netherlands, The Netherlands Organisation for Health Research and Development (ZonMw)
- United Kingdom, Medical Research Council
- Germany, German Federal ministry of Education and Research (BMBF)
- Luxembourg, National Research Fund (FNR)
- European Unions Horizon research and innovation programme [643417]
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.
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