Altered CpG methylation in sporadic Alzheimer's disease is associated with APP and MAPT dysregulation
Altered CpG methylation in sporadic Alzheimer's disease is associated with APP and MAPT dysregulation
复制标题
DOI：
10.1093/hmg/ddt451
复制
发表时间：
2014-02-01
影响因子：
3.5
通讯作者：
Tsuji, Shoji
中科院分区：
文献类型：
--
作者：
Iwata, Atsushi;Nagata, Kenichi;Tsuji, Shoji
阿尔茨海默病（AD）病理的标志是淀粉样蛋白β (A β)和磷酸化tau的积累，它们分别由淀粉样蛋白前体蛋白（APP）和微管相关蛋白tau （MAPT）基因编码。不到5%的AD病例是家族性的，即由APP、PSEN1或PSEN2突变引起。在他们身上发现的几乎所有突变都与A β(1-42)的过量产生有关，这很容易聚集。虽然这些基因没有突变，但它们或相关基因的功能在散发性阿尔茨海默病中也可能受到损害。在本研究中，对死后大脑进行焦磷酸测序分析，发现AD大脑的APP、MAPT和GSK3B基因存在CpG甲基化异常。这些变化通过新开发的体外特异性DNA甲基化系统进一步评估，该系统反过来突出了APP和MAPT的表达增强。死后脑的细胞核分选结果显示，APP和MAPT在神经元细胞和非神经元细胞中均发生甲基化变化，而GSK3B在非神经元细胞中发生异常甲基化。进一步分析显示APP CpG甲基化异常与载脂蛋白E epsilon 4等位基因（APOE epsilon 4）阴性病例之间存在关联。正常神经元中少量高度甲基化的神经元的存在导致APP和MAPT CpGs的甲基化差异，因此异常甲基化的细胞可能损害神经回路和/或作为异常蛋白质繁殖的“种子细胞”。我们的研究结果提供了家族性阿尔茨海默病基因与散发性神经病理之间的联系，从而强调了散发性阿尔茨海默病的表观遗传病理机制。
The hallmark of Alzheimer's disease (AD) pathology is an accumulation of amyloid beta (A beta) and phosphorylated tau, which are encoded by the amyloid precursor protein (APP) and microtubule-associated protein tau (MAPT) genes, respectively. Less than 5% of all AD cases are familial in nature, i.e. caused by mutations in APP, PSEN1 or PSEN2. Almost all mutations found in them are related to an overproduction of A beta(1-42), which is prone to aggregation. While these genes are mutation free, their function, or those of related genes, could be compromised in sporadic AD as well. In this study, pyrosequencing analysis of post-mortem brains revealed aberrant CpG methylation in APP, MAPT and GSK3B genes of the AD brain. These changes were further evaluated by a newly developed in vitro-specific DNA methylation system, which in turn highlighted an enhanced expression of APP and MAPT. Cell nucleus sorting of post-mortem brains revealed that the methylation changes of APP and MAPT occurred in both neuronal and non-neuronal cells, whereas GSK3B was abnormally methylated in non-neuronal cells. Further analysis revealed an association between abnormal APP CpG methylation and apolipoprotein E epsilon 4 allele (APOE epsilon 4)-negative cases. The presence of a small number of highly methylated neurons among normal neurons contribute to the methylation difference in APP and MAPT CpGs, thus abnormally methylated cells could compromise the neural circuit and/or serve as 'seed cells' for abnormal protein propagation. Our results provide a link between familial AD genes and sporadic neuropathology, thus emphasizing an epigenetic pathomechanism for sporadic AD.