The Epigenetics of Alzheimer's Disease

描述(由申请人提供)：阿尔茨海默病(AD)是一种与年龄相关的神经退行性疾病，与严重的记忆障碍有关，目前还没有治愈的方法。尽管遗传证据有力地支持了β-淀粉样蛋白(A？)在疾病中的作用，但A？与神经变性/记忆损伤之间的机制还远不清楚。在与阿尔茨海默病的斗争中，我们必须扩大我们的方法，使其超越目前对淀粉样蛋白病理的关注。对抗阿尔茨海默病症状的新治疗方法的研究表明，增加染色质重塑和基因表达具有有益的效果。我们已经证明，在AD的CK-p25小鼠模型中，组蛋白脱乙酰酶(HDAC)的小分子抑制剂即使在发生严重的神经元丢失后也能恢复学习能力。组蛋白I类脱乙酰酶HDAC2参与了海马区依赖的学习和记忆的调节。HDAC2与突触形成和突触可塑性相关基因的调控元件结合，并在CK-p25和5XFAD小鼠AD模型中上调。这些发现导致了这样的想法，在神经退化过程中，由HDAC2上调介导的表观遗传格局改变，可能会抑制维持突触可塑性和记忆功能所需的基因产物的表达。因此，抑制HDAC2，即使在神经变性开始之后，也可以改善存活神经元的功能。在目前的应用中，我们将检验一种新的疾病机制，涉及HDAC2介导的表观遗传格局的改变，是阿尔茨海默病认知障碍和突触功能障碍的基础。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with severe memory impairments for which, currently, there is no cure. Although the role of beta-amyloid (A¿) in the disease is strongly supported by genetic evidence, the mechanism between A¿ and neurodegeneration/memory impairments is far from clear. In combating AD, it is imperative that we expand our approach beyond the current focus upon amyloid pathology. Research into novel therapeutic approaches to combat the symptoms of AD has revealed beneficial effects of increased chromatin remodeling and gene expression. We have shown that small molecule inhibitors of histone deacetylases (HDACs) restore learning ability in the CK-p25 mouse model of AD even after severe neuronal loss has occurred. The class I histone deacetylase, HDAC2, has been shown to participate in the regulation of hippocampal-dependent learning and memory. HDAC2 binds to the regulatory elements of genes implicated in synapse formation and synaptic plasticity, and is upregulated in both the CK-p25 and the 5XFAD mouse models of AD. These findings have led to the idea that, during neurodegeneration, an altered epigenetic landscape, mediated by HDAC2 up-regulation, may repress the expression of gene products necessary for maintaining synaptic plasticity and memory functions. Thus, inhibition of HDAC2, even after the onset of neurodegeneration, can improve the function of surviving neurons. In the current application, we will test the hypothesis that a novel disease mechanism, involving HDAC2 mediated alteration of the epigenetic landscape, underlies the cognitive impairment and synaptic dysfunction of Alzheimer's disease.