Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer's disease.
Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer's disease.
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DOI：
10.1016/j.mcn.2017.11.002
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Rutten BPF
中科院分区：
文献类型：
--
作者：
Lardenoije R;van den Hove DLA;Havermans M;van Casteren A;Le KX;Palmour R;Lemere CA;Rutten BPF
衰老和阿尔茨海默病(AD)都与广泛的表观遗传学变化有关，大多数证据表明AD的整体低甲基化。然而，目前尚不清楚这些与年龄相关的表观遗传学变化如何与AD动物模型中表达的分子异常有关。在这里，我们研究了一系列AD动物模型中DNA甲基化和羟甲基化的表观遗传标志物的年龄相关变化，以及它们与淀粉样斑块负荷的相关性。研究了J20、APP/PS1dE9和3xTg-AD三种转基因小鼠模型，以及加勒比海牡蛎(一种非转基因的非人类灵长类AD模型)。在J20小鼠模型中，齿状回(DG)的DNA甲基化水平随年龄增长而降低，DG和山角(CA)3的DNA甲基化与羟甲基化比率降低。在3xTg-AD小鼠中，DG和CA1-2的DNA甲基化水平随年龄增长而增加。APP/PS1dE9小鼠和非人灵长类动物模型中未发现明显的年龄相关变化。在J20模型中，海马斑块负荷与DG中DNA甲基化呈显著负相关，与DG和CA3中DNA甲基化比率呈负相关。在APP/PS1dE9模型中，CA3区的DNMT3A水平与斑块负荷呈负相关，DG和CA3区的DNMT3A水平与斑块负荷呈负相关。因此，只有J20模型显示出与年龄相关的全球DNA甲基化减少，而在3xTg-AD模型中观察到DNA超甲基化。鉴于动物模型之间的这些差异，未来的研究需要进一步阐明不同的AD相关遗传变异对年龄相关表观遗传学变化的贡献。
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 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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影响因子：
4.2
作者：
Chouliaras L;van den Hove DL;Kenis G;Keitel S;Hof PR;van Os J;Steinbusch HW;Schmitz C;Rutten BP
通讯作者：
Rutten BP
影响因子：
3.9
作者：
Budden DM;Hurley DG;Crampin EJ
通讯作者：
Crampin EJ
影响因子：
5.3
作者：
Bradley-Whitman, M. A.;Lovell, M. A.
通讯作者：
Lovell, M. A.
影响因子：
3.5
作者：
Fuso, A;Seminara, L;Scarpa, S
通讯作者：
Scarpa, S
影响因子：
4
作者：
Cadena-del-Castilloa, Carla;Valdes-Quezada, Christian;Recillas-Targa, Felix
通讯作者：
Recillas-Targa, Felix