Age-specific epigenetic drift in late-onset Alzheimer's disease.
Age-specific epigenetic drift in late-onset Alzheimer's disease.
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DOI：
10.1371/journal.pone.0002698
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发表时间：
2008-07-16
期刊：
影响因子：
3.7
通讯作者：
Schumacher, Axel
中科院分区：
文献类型：
--
作者：
Wang, Sun-Chong;Oelze, Beatrice;Schumacher, Axel
尽管付出了巨大的研究努力，但大多数晚发性阿尔茨海默病（LOAD）病例仍然无法解释，目前的生物医学科学距离揭示明确的危险因素以帮助诊断、预防和治疗该疾病的最终目标还有很长的路要走。目前关于LOAD发展的理论取决于阿尔茨海默病主要由遗传原因引起的前提。然而，复杂的非孟德尔疾病病因学表明可能涉及表观遗传成分。利用MALDI-TOF质谱分析死后脑样本和淋巴细胞，我们对12个潜在阿尔茨海默病易感位点的DNA甲基化进行了分析。在LOAD脑样本中，我们发现了明显的年龄特异性表观遗传漂变，支持表观遗传效应在疾病发展中的潜在作用。此外，我们发现一些参与淀粉样蛋白-β加工的基因（PSEN1， APOE）和甲基化稳态（MTHFR, DNMT1）在个体间表现出显著的表观遗传变异性，这可能有助于LOAD易感性。发现APOE基因具有双峰结构，具有低甲基化的CpG-poor启动子和完全甲基化的3 ' -CpG-island，其中包含ε4单倍型序列，这是唯一无可争议的遗传风险因素。cpg岛的异常表观遗传控制可能导致LOAD病理。我们认为，表观遗传漂变可能是使个体易患LOAD并促进疾病进程的一个重要机制。
Despite an enormous research effort, most cases of late-onset Alzheimer's disease (LOAD) still remain unexplained and the current biomedical science is still a long way from the ultimate goal of revealing clear risk factors that can help in the diagnosis, prevention and treatment of the disease. Current theories about the development of LOAD hinge on the premise that Alzheimer's arises mainly from heritable causes. Yet, the complex, non-Mendelian disease etiology suggests that an epigenetic component could be involved. Using MALDI-TOF mass spectrometry in post-mortem brain samples and lymphocytes, we have performed an analysis of DNA methylation across 12 potential Alzheimer's susceptibility loci. In the LOAD brain samples we identified a notably age-specific epigenetic drift, supporting a potential role of epigenetic effects in the development of the disease. Additionally, we found that some genes that participate in amyloid-β processing (PSEN1, APOE) and methylation homeostasis (MTHFR, DNMT1) show a significant interindividual epigenetic variability, which may contribute to LOAD predisposition. The APOE gene was found to be of bimodal structure, with a hypomethylated CpG-poor promoter and a fully methylated 3′-CpG-island, that contains the sequences for the ε4-haplotype, which is the only undisputed genetic risk factor for LOAD. Aberrant epigenetic control in this CpG-island may contribute to LOAD pathology. We propose that epigenetic drift is likely to be a substantial mechanism predisposing individuals to LOAD and contributing to the course of disease.
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影响因子：
2.4
作者：
Lehmann, M;Gottfries, CG;Regland, B
通讯作者：
Regland, B
DOI：
10.1002/ajmg.b.30350
发表时间：
2006-07-05
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作者：
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影响因子：
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作者：
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通讯作者：
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