Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, MD 21201, USA.
Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, MD 21201, USA.
Curr Alzheimer Res. 2022;19(7):530-540. doi: 10.2174/1567205019666220831125142.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and ApoE4 variants are significant risk factors for AD. Epigenetic modifications are involved in AD pathology. However, it is unclear whether DNA/RNA methylation plays a role in AD pathology, and dysregulation of DNA/RNA methylation occurs in ApoE4 carriers.
The present study aimed to determine whether dysregulation of DNA/RNA methylation is present in the brains of ApoE4 carriers and AD patients.
In this study, postmortem brain tissues from carriers of ApoE4 and ApoE3, from AD and non- AD controls, were used in the analysis of DNA/RNA methylation, methyltransferases, and their demethylases.
Immunofluorescence staining indicates that RNA methylation is suppressed in ApoE4 carriers. Further analysis shows that the expression of RNA methyltransferases and an RNA methylation reader is suppressed in ApoE4 carriers, whereas RNA demethylase expression is increased. RNA hypomethylation occurs in NeuN+ neurons in ApoE4 carriers and AD patients. Furthermore, in ApoE4 carriers, both DNA methyltransferases and demethylases are downregulated, and overall DNA methylation levels are unchanged.
Our finding indicates that RNA methylation decreased in ApoE4 carriers before AD pathology and AD individuals. The expression of RNA methyltransferases and RNA methylation reader is inhibited, and RNA demethylase is upregulated in ApoE4 carriers, which leads to suppression of RNA methylation, and the suppression precedes the AD pathogenesis and persists through AD pathology.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，ApoE4 变体是 AD 的重要危险因素。表观遗传修饰参与 AD 病理学。然而，目前尚不清楚 DNA/RNA 甲基化是否在 AD 病理学中发挥作用，并且 ApoE4 携带者中存在 DNA/RNA 甲基化失调。
本研究旨在确定 ApoE4 携带者和 AD 患者的大脑中是否存在 DNA/RNA 甲基化失调。
本研究分析了 ApoE4 携带者、ApoE3 携带者、AD 患者和非 AD 对照者死后脑组织中的 DNA/RNA 甲基化、甲基转移酶及其去甲基酶。
免疫荧光染色表明 ApoE4 携带者的 RNA 甲基化受到抑制。进一步分析表明，ApoE4 携带者的 RNA 甲基转移酶和 RNA 甲基化阅读器表达受到抑制，而 RNA 去甲基酶表达增加。ApoE4 携带者和 AD 患者的 NeuN+神经元中发生 RNA 低甲基化。此外，ApoE4 携带者中 DNA 甲基转移酶和去甲基酶均下调，总体 DNA 甲基化水平不变。
我们的发现表明，在 AD 病理学和 AD 个体之前，ApoE4 携带者的 RNA 甲基化就已经降低。ApoE4 携带者中 RNA 甲基转移酶和 RNA 甲基化阅读器的表达受到抑制，RNA 去甲基酶上调，导致 RNA 甲基化抑制，这种抑制先于 AD 发病机制并持续存在于 AD 病理过程中。
