Inhibitors of Class 1 Histone Deacetylases Reverse Contextual Memory Deficits in a Mouse Model of Alzheimer's Disease
Inhibitors of Class 1 Histone Deacetylases Reverse Contextual Memory Deficits in a Mouse Model of Alzheimer's Disease
复制标题
DOI：
10.1038/npp.2009.197
复制
发表时间：
2010-03-01
影响因子：
7.6
通讯作者：
Rumbaugh, Gavin
中科院分区：
文献类型：
--
作者：
Kilgore, Mark;Miller, Courtney A.;Rumbaugh, Gavin
阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，其临床特征是认知障碍，其进展为痴呆和死亡。AD的最早症状表现为相对单纯的记忆提取缺陷。因此，通过挽救记忆缺陷来干预AD早期阶段的药物治疗可能是减缓甚至逆转疾病进展的有希望的疗法。在这项研究中，我们测试了系统性组蛋白去乙酰化酶抑制剂（HDACi）治疗在AD小鼠模型中挽救认知缺陷的潜力。APPswe/PS1 dE 9小鼠在6个月大时开始表现出明显的背景记忆障碍。慢性HDACi注射（2-3周）不会改变正常小鼠的背景记忆形成，但对转基因动物有深远的影响。注射丙戊酸钠、丁酸钠或伏立诺他（辛二酰苯胺异羟肟酸; Zolinzas（R））完全恢复了这些突变小鼠的上下文记忆。HDACi处理的转基因小鼠的进一步行为测试表明，新巩固的记忆在2周内稳定维持。对丙戊酸钠、丁酸钠和伏立诺他的HDAC亚型选择性特征的测量显示，1类HDAC（HDAC 1、2、3、8）的常见抑制作用对IIa类HDAC家族成员（HDAC 4、5、7、9）几乎没有影响，并且仅伏立诺他抑制HDAC 6。这些临床前结果表明，I类HDAC亚型的靶向抑制是治疗与早期AD相关的认知缺陷的有希望的途径。Neuropsychopharmacology（2010）35，870-880; doi：10.1038/npp.2009.197;在线发表于2009年12月9日
Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by cognitive impairments that progress to dementia and death. The earliest symptoms of AD present as a relatively pure deficit in memory retrieval. Therefore, drug treatments that intervene in the early stages of AD by rescuing memory deficits could be promising therapies to slow, or even reverse progression of the disease. In this study, we tested the potential of systemic histone deacetylase inhibitor (HDACi) treatment to rescue cognitive deficits in a mouse model of AD. APPswe/PS1dE9 mice showed pronounced contextual memory impairments beginning at 6 months of age. Chronic HDACi injections (2-3 weeks) did not alter contextual memory formation in normal mice, but had profound effects in transgenic animals. Injections of sodium valproate, sodium butyrate, or vorinostat (suberoylanilide hydroxamic acid; Zolinzas (R)) completely restored contextual memory in these mutant mice. Further behavioral testing of the HDACi-treated transgenic mice showed that the newly consolidated memories were stably maintained over a 2-week period. Measurement of the HDAC isoform selectivity profile of sodium valproate, sodium butyrate, and vorinostat revealed the common inhibition of class 1 HDACs (HDAC1, 2, 3, 8) with little effect on the class IIa HDAC family members (HDAC4, 5, 7, 9) and inhibition of HDAC6 only by vorinostat. These preclinical results indicate that targeted inhibition of class I HDAC isoforms is a promising avenue for treating the cognitive deficits associated with early stage AD. Neuropsychopharmacology (2010) 35, 870-880; doi:10.1038/npp.2009.197; published online 9 December 2009