DNA methylation in the hippocampus in rodent and primate models of aging and Alzheimer’s disease
AbstractWith the aging of the world’s population, Alzheimer’s disease (AD) is a growing problem. It is caused by pathological hallmarks including amyloid β plaques and neurofibrillary tangles, but the underlying molecular mechanisms are unknown. DNA methylation, the binding of a methyl group to cytosine in the DNA, has been suggested to play a role in the development of AD. It is catalyzed by the enzyme DNA methyltransferase (DNMT) and creases a 5-methylcytosine (5mC), which generally represses gene expression. 5mC can be converted into 5hmC by ten eleven translocation (TET) enzymes and this is believed to increase gene expression. DNA methylation, DNA hydroxymethylation and DNMT3A, a member of the DNMT family involved in de novo DNA methylation, are suggested to influence cognitive functions, but their exact role in the onset and development of AD remains unknown. In this study, possible changes in these epigenetic markers in the hippocampal sub-regions (cornu ammonis 1, 2 and 3 (CA1, 2 and 3) and dentate gyrus (DG)) of several animal models for AD are examined. 5mC levels in the DG of J20 were shown to decrease with aging and Dnmt3a levels in the CA1-2 of these mice showed an age-related increase. In contrast to the J20 mice, 3xTgAD mice showed an increase in 5mC in the DG as well as an increase in Dnmt3a levels. In both the APP/PS1 mouse model and the vervets, no significant increases or decreases were detected. These results show that there are major differences in DNA methylation in hippocampal sub-regions between different animal models for AD.
Bennett DA, Yu L, Yang J, Srivastava GP, Aubin C, De Jager PL. Epigenomics of Alzheimer’s disease. Transl Res. 2015;165(1):200-20.
Xu X. DNA methylation and cognitive aging. Oncotarget. 2015.
Wang X, Michalis ML, Michaelis EK. Functional genomics of brain aging and Alzheimer’s disease: focus on selective neuronal vulnerability. Curr Genomics. 2010;11(8):618-33.
Auclair G, Weber M. Mechanisms of DNA methylation and demethylation in mammals. Biochimie. 2012;94(11):2202-11.
Chouliaras L, van den Hove DL, Kenis G, et al. Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction. Curr Alzheimer Res. 2012;9(5):536-44.
Lardenoije R, Iatrou A, Kenis G, et al. The epigenetics of aging and neurodegeneration. Progress in Neurobiology. 2015 [Epub ahead of print].
Coppieters N, Dieriks BV, Lill C, et al. Global changes in DNA methylation and hydroxymethylation in Alzheimer’s disease human brain. Neurobiol Aging. 2014;35(6):1334-44.