Liu Dan, Tang Hui, Li Xin-Yan, Deng Man-Fei, Wei Na, Wang Xiong, Zhou Ya-Fan, Wang Ding-Qi, Fu Peng, Wang Jian-Zhi, Hébert Sébastien S, Chen Jian-Guo, Lu Youming, Zhu Ling-Qiang
The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Mol Ther. 2017 Mar 1;25(3):752-764. doi: 10.1016/j.ymthe.2017.01.018. Epub 2017 Feb 13.
Histone deacetylase 2 (HDAC2) plays a major role in the epigenetic regulation of gene expression. Previous studies have shown that HDAC2 expression is strongly increased in Alzheimer's disease (AD), a major neurodegenerative disorder and the most common form of dementia. Moreover, previous studies have linked HDAC2 to Aβ overproduction in AD; however, its involvement in tau pathology and other memory-related functions remains unclear. Here, we show that increased HDAC2 levels strongly correlate with phosphorylated tau in a mouse model of AD. HDAC2 overexpression induced AD-like tau hyperphosphorylation and aggregation, which were accompanied by a loss of dendritic complexity and spine density. The ectopic expression of HDAC2 resulted in the deacetylation of the hepatocyte nuclear factor 4α (HNF-4A) transcription factor, which disrupted its binding to the miR-101b promoter. The suppression of miR-101b caused an upregulation of its target, AMP-activated protein kinase (AMPK). The introduction of miR-101b mimics or small interfering RNAs (siRNAs) against AMPK blocked HDAC2-induced tauopathy and dendritic impairments in vitro. Correspondingly, miR-101b mimics or AMPK siRNAs rescued tau pathology, dendritic abnormalities, and memory deficits in AD mice. Taken together, the current findings implicate the HDAC2/miR-101/AMPK pathway as a critical mediator of AD pathogenesis. These studies also highlight the importance of epigenetics in AD and provide novel therapeutic targets.
组蛋白去乙酰化酶2（HDAC2）在基因表达的表观遗传调控中起主要作用。先前的研究表明，在阿尔茨海默病（AD）中，HDAC2的表达显著增加，AD是一种主要的神经退行性疾病，也是最常见的痴呆形式。此外，先前的研究已将HDAC2与AD中β淀粉样蛋白（Aβ）的过度产生联系起来；然而，其在tau蛋白病变及其他与记忆相关功能中的作用仍不清楚。在此，我们表明，在AD小鼠模型中，HDAC2水平升高与磷酸化tau蛋白密切相关。HDAC2的过表达诱导了类似AD的tau蛋白过度磷酸化和聚集，同时伴有树突复杂性和棘密度的降低。HDAC2的异位表达导致肝细胞核因子4α（HNF-4A）转录因子去乙酰化，从而破坏其与miR-101b启动子的结合。miR-101b的抑制导致其靶标AMP激活蛋白激酶（AMPK）上调。引入miR-101b模拟物或针对AMPK的小干扰RNA（siRNA）可在体外阻断HDAC2诱导的tau蛋白病变和树突损伤。相应地，miR-101b模拟物或AMPK siRNA可挽救AD小鼠的tau蛋白病变、树突异常和记忆缺陷。综上所述，目前的研究结果表明HDAC2/miR-101/AMPK通路是AD发病机制的关键介质。这些研究还突出了表观遗传学在AD中的重要性，并提供了新的治疗靶点。
