Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease.
Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease.
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DOI：
10.1016/j.expneurol.2012.10.005
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发表时间：
2013-01
影响因子：
5.3
通讯作者：
Hoe, Hyang-Sook
中科院分区：
文献类型：
--
作者：
Sung, You Me;Lee, Taehee;Yoon, Hyejin;DiBattista, Amanda Marie;Song, Jung Min;Sohn, Yoojin;Moffat, Emily Isabella;Turner, R. Scott;Jung, Mira;Kim, Jungsu;Hoe, Hyang-Sook
关键词：
组蛋白去乙酰化酶抑制剂（HDACIs）通过干扰HDAC的正常功能来改变基因表达。鉴于其降低Aβ水平的能力，HDACIs是阿尔茨海默病（AD）的潜在治疗领域。然而，目前尚不清楚HDACIs如何改变Aβ水平。我们开发了两种新的HDAC抑制剂，具有改进的药理学特性，例如更长的半衰期和更大的血脑屏障渗透性：基于巯基乙酰胺的II类HDACI（编码为W2）和基于异羟肟酸的I类和IIHDACI（编码为I2），并研究了它们如何影响Aβ水平和认知。HDACI W2降低Aβ40和Aβ42的水平。HDACI I2也降低Aβ40，但不降低Aβ42。我们系统地研究了HDACIs W2和I2降低Aβ水平的分子机制。HDACI W2降低γ-分泌酶组分的基因表达，并增加Aβ降解酶Mmp 2。类似地，HDACI I2降低β-和γ-分泌酶组分的表达，并增加Aβ降解酶的mRNA水平。HDACI W2还显著降低了老年hAPP 3x Tg AD小鼠的Aβ水平并挽救了学习和记忆缺陷。此外，我们发现新的HDACI W2降低了Thr 181处的tau磷酸化，这是以前对HDACI未知的效果。总的来说，这些数据表明，II类HDACl可以作为AD的新的治疗策略。
Histone deacetylase inhibitors (HDACIs) alter gene expression epigenetically by interfering with the normal functions of HDAC. Given their ability to decrease Aβ levels, HDACIs area potential treatment for Alzheimer's disease (AD). However, it is unclear how HDACIs alter Aβ levels. We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood-brain barrier: mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as I2) and investigated how they affect Aβ levels and cognition. HDACI W2 decreased Aβ40 and Aβ42 in vitro. HDACI I2 also decreased Aβ40, but not Aβ42. We systematically examined the molecular mechanisms by which HDACIs W2 and I2 can decrease Aβ levels. HDACI W2 decreased gene expression of γ-secretase components and increased the Aβ degradation enzyme Mmp2. Similarly, HDACI I2 decreased expression of β- and γ-secretase components and increased mRNA levels of Aβ degradation enzymes. HDACI W2 also significantly decreased Aβ levels and rescued learning and memory deficits in aged hAPP 3x Tg AD mice. Furthermore, we found that the novel HDACI W2 decreased tau phosphorylation at Thr181, an effect previously unknown for HDACIs. Collectively, these data suggest that class II HDACls may serve as a novel therapeutic strategy for AD.
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影响因子：
5.8
作者：
Konsoula, Roula;Jung, Mira
通讯作者：
Jung, Mira
DOI：
10.1097/00005072-199609000-00003
发表时间：
1996-09-01
影响因子：
3.2
作者：
Hempen, B;Brion, JP
通讯作者：
Brion, JP
影响因子：
2.1
作者：
Iqbal, Khalid;Grundke-Iqbal, Inge
通讯作者：
Grundke-Iqbal, Inge
影响因子：
5.7
作者：
Konsoula, Zacharoula;Cao, Hong;Jung, Mira
通讯作者：
Jung, Mira
影响因子：
3.4
作者：
Kozikowski, Alan P.;Chen, Yihua;Subhasish, Tapadar;Lewin, Nancy E.;Blumberg, Peter M.;Zhong, Zhenyu;D'Annibale, Melissa A.;Wang, Weng-Long;Shen, Yong;Langley, Brett
通讯作者：
Langley, Brett