Epigenetic Alterations in Alzheimer's Disease.
Epigenetic Alterations in Alzheimer's Disease.
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DOI：
10.3389/fnbeh.2015.00347
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发表时间：
2015
影响因子：
3
通讯作者：
Gräff J
中科院分区：
文献类型：
--
作者：
Sanchez-Mut JV;Gräff J
阿尔茨海默病（AD）是西方社会痴呆症的主要原因。它的进展无症状，在几十年前被诊断时，治疗策略已变得不可行。虽然有几种基因改变与AD相关，但绝大多数AD病例没有显示出强有力的遗传基础，因此被认为是非遗传因素的结果。表观遗传机制允许在特定的遗传背景上整合持久的非遗传输入，并且最近，已经描述了越来越多的AD中的表观遗传改变。例如，衰老过程中表观遗传机制失调的积累，AD的主要危险因素，可能促进疾病的发作。同样，表观遗传机制的几种酶的突变与AD中改变的神经退行性过程相关，例如学习和记忆形成受损。全基因组和基因座特异性表观遗传改变也有报道，几个表观遗传失调的基因被独立的研究小组验证。从这些研究中，出现了AD与DNA超甲基化和组蛋白脱乙酰化相关的图像，表明AD中的染色质状态普遍受到抑制，表观遗传可塑性降低。在这里，我们回顾了这些最近的研究结果，并讨论了几个技术和方法上的考虑，这是必要的，他们的正确解释。我们还特别关注潜在的实施和理论框架，我们希望这将有助于更好地指导未来的研究，旨在解开AD的表观遗传参与。
Alzheimer’s disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD.