Karagiannis Tom C, Ververis Katherine
Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.
Pathobiol Aging Age Relat Dis. 2012;2. doi: 10.3402/pba.v2i0.14980. Epub 2012 Feb 20.
Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.
阿尔茨海默病是一种非常常见的进行性神经退行性疾病，会影响大脑中的学习和记忆中枢。该疾病的标志是由异常磷酸化的tau蛋白形成的β-淀粉样神经炎性斑块和神经原纤维缠结的积累。阿尔茨海默病目前无法治愈，因此人们对开发新的潜在治疗方法有着浓厚的兴趣。诸如沉默调节蛋白调节剂和组蛋白去乙酰化酶抑制剂等染色质修饰化合物已在阿尔茨海默病模型中进行了评估，取得了一些有前景的结果。例如，天然抗氧化剂和沉默调节蛋白1激活剂白藜芦醇已在该疾病的动物模型中显示出有益效果。同样，包括曲古抑菌素A、辛二酰苯胺异羟肟酸、丙戊酸和苯丁酸盐在内的多种组蛋白去乙酰化酶抑制剂在阿尔茨海默病模型中也显示出了有前景的结果。这些有益效果包括减少β-淀粉样蛋白的产生和稳定tau蛋白。在这篇综述中，我们概述了组蛋白去乙酰化酶，重点关注已被确定在阿尔茨海默病病理生物学中起重要作用的酶。此外，我们还讨论了用调节组蛋白去乙酰化酶的染色质修饰化合物进行药物干预的潜力。
