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，目前还没有治愈方法。虽然β-淀粉样蛋白（A <$）在疾病中的作用得到了遗传证据的有力支持，但A <$和神经变性/记忆障碍之间的机制还远不清楚。在对抗AD时，我们必须将我们的方法扩展到目前对淀粉样蛋白病理学的关注之外。对对抗AD症状的新治疗方法的研究已经揭示了增加的染色质重塑和基因表达的有益作用。我们已经表明，组蛋白脱乙酰酶（HDAC）的小分子抑制剂恢复AD的CK-p25小鼠模型的学习能力，即使在严重的神经元损失已经发生。I类组蛋白去乙酰化酶HDAC 2已被证明参与调节海马依赖性学习和记忆。HDAC 2与突触形成和突触可塑性相关基因的调控元件结合，并且在AD的CK-p25和5XFAD小鼠模型中均上调。这些发现导致了这样的想法，即在神经退行性疾病期间，由HDAC 2上调介导的改变的表观遗传景观可能抑制维持突触可塑性和记忆功能所必需的基因产物的表达。因此，即使在神经变性发作之后，HDAC 2的抑制也可以改善存活神经元的功能。在本申请中，我们将测试一种新的疾病机制的假设，涉及HDAC 2介导的表观遗传景观的改变，是阿尔茨海默病的认知障碍和突触功能障碍的基础。 公共卫生相关性：阿尔茨海默氏病（AD）是一种与年龄相关的神经退行性疾病，与严重的记忆障碍相关，目前还没有治愈的方法。我们已经表明，组蛋白脱乙酰酶（HDAC）的小分子抑制剂恢复AD的CK-p25小鼠模型的学习能力，即使在严重的神经元损失已经发生。目前的申请将测试一种新的疾病机制，涉及表观遗传学，是阿尔茨海默病的认知障碍和突触功能障碍的基础的假设。

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. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with severe memory impairments for which, currently, there is no cure. 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 current application will test the hypothesis that a novel disease mechanism, involving epigenetics, underlies the cognitive impairment and synaptic dysfunction of Alzheimer's disease.