title: Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer's Disease.
abstract: 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.
authors.affiliation: 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.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xin-Yan
authors.initials: XY
authors.lastname: Li
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Man-Fei
authors.initials: MF
authors.lastname: Deng
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Ya-Fan
authors.initials: YF
authors.lastname: Zhou
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Ding-Qi
authors.initials: DQ
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, CHUL, Québec, QC G1V 4G2, Canada; Département de psychiatrie et neurosciences, Université Laval, Québec, QC G1V 0A6, Canada.
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Youming
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 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. Electronic address: zhulq@mail.hust.edu.cn.
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001665:Binding Sites; D016384:Consensus Sequence; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation; D020868:Gene Silencing; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; C581233:MIRN101 microRNA, mouse; D035683:MicroRNAs; D016875:tau Proteins; D055372:AMP-Activated Protein Kinases; D056464:Histone Deacetylase 2
keywords: AMPK; Alzheimer’s disease; HDAC2; HNF-4A; dendritic spines; miR-101b; tauopathy