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.

衰老和阿尔茨海默病 (AD) 都与广泛的表观遗传变化相关，大多数证据表明 AD 中存在整体低甲基化。然而，目前尚不清楚这些与年龄相关的表观遗传变化如何与 AD 动物模型中表达的分子畸变相关。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记与年龄相关的变化，以及它们与淀粉样斑块负荷的相关性。研究了三种转基因小鼠模型，包括 J20、APP/PS1dE9 和 3xTg-AD 模型，以及加勒比长尾黑颚猴（AD 的非转基因非人灵长类动物模型）。在 J20 小鼠模型中，在齿状回 (DG) 中发现 DNA 甲基化与年龄相关的下降，并且在 DG 和角 (CA) 中发现 DNA 甲基化与羟甲基化之间的比率下降 3。 在 3xTg 中-AD小鼠，在DG和CA1-2中发现了与年龄相关的DNA甲基化增加。在 APP/PS1dE9 小鼠和非人灵长类动物模型中没有发现与年龄相关的显着变化。在J20模型中，海马斑块负荷与DG中的DNA甲基化呈显着负相关，与DG和CA3中的比率呈负相关。对于 APP/PS1dE9 模型，在 CA3 中观察到该比率与噬菌斑负载之间呈负相关，并且在 DG 和 CA3 中观察到 DNA 甲基转移酶 3A (DNMT3A) 水平与噬菌斑负载之间呈负相关。因此，只有 J20 模型显示出与年龄相关的整体 DNA 甲基化减少，而在 3xTg-AD 模型中观察到 DNA 高甲基化。 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变化的贡献。