Journal
MOLECULAR THERAPY
Volume 25, Issue 3, Pages 752-764Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2017.01.018
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Funding
- National Natural Science Foundation of China [31571039, 91632114, 81400899, 81361120245, 81400897, 81400963]
- Top-Notch Young Talents Program of China
- Program of Outstanding Youth of Hubei Province, China [2014CFA017]
- Academic Frontier Youth Team of Huazhong University of Science and Technology
- Program for Changjiang Scholars and Innovative Research Team in University [IRT13016]
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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 A beta 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 4 alpha (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.
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