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，目前尚无治愈方法。尽管遗传证据强烈支持β -淀粉样蛋白（A¿）在该疾病中的作用，但A¿与神经变性/记忆障碍之间的机制尚不清楚。在对抗阿尔茨海默病的过程中，我们必须扩展我们的方法，超越目前对淀粉样蛋白病理的关注。对对抗AD症状的新治疗方法的研究已经揭示了染色质重塑和基因表达增加的有益作用。我们已经证明，即使发生严重的神经元丧失，组蛋白去乙酰化酶（hdac）的小分子抑制剂也能恢复CK-p25 AD小鼠模型的学习能力。I类组蛋白去乙酰化酶HDAC2已被证明参与海马依赖性学习和记忆的调节。HDAC2与突触形成和突触可塑性相关基因的调控元件结合，在CK-p25和5XFAD AD小鼠模型中均上调。这些发现表明，在神经退行性变过程中，由HDAC2上调介导的表观遗传景观改变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，抑制HDAC2，即使在神经退行性疾病发生后，也可以改善存活神经元的功能。在当前的应用中，我们将验证一种新的疾病机制，包括HDAC2介导的表观遗传景观的改变，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.