Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer's Disease.

TitleTargeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer's Disease.
Publication TypeJournal Article
Year of Publication2017
AuteursLiu, D, Tang, H, Li, X-Y, Deng, M-F, Wei, N, Wang, X, Zhou, Y-F, Wang, D-Q, Fu, P, Wang, J-Z, Hébert, SS, Chen, J-G, Lu, Y, Zhu, L-Q
JournalMol Ther
Volume25
Issue3
Pagination752-764
Date Published2017 Mar 01
ISSN1525-0024
KeywordsAlzheimer Disease, AMP-Activated Protein Kinases, Animals, Binding Sites, Consensus Sequence, Dendrites, Disease Models, Animal, Gene Expression, Gene Expression Regulation, Gene Silencing, Hepatocyte Nuclear Factor 4, Histone Deacetylase 2, Memory Disorders, Mice, MicroRNAs, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Pyramidal Cells, tau Proteins, Tauopathies
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.

DOI10.1016/j.ymthe.2017.01.018
Alternate JournalMol. Ther.
PubMed ID28202389
PubMed Central IDPMC5363202