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 Ab overproduction in AD; however, its involvement in tau pathology and other memory-related functions remains unclear. Here, we first demonstrate that the HDAC2 levels are positively correlated with tau hyperphosphorylation in AD mice, and the overexpression of HDAC2, in contrast to HDAC1 or HDAC3, was sufficient to promote tau hyperphosphorylation, tau aggregation, and dendritic impairments in vivo. We then show that HDAC2 overexpression reduced the acetylation of hepatocyte nuclear factor 4α (HNF-4A), which inhibited its binding to the promoter region of miR-101b. The suppression of miR-101b leads to the upregulation of adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) expression at the post-transcriptional level. We subsequently antagonized this disease-modifying signal via the specific introduction of miR-101b mimics or silencing AMPK expression in cultured neurons and determined that tau hyperphosphorylation, aggregation and dendritic impairments induced by HDAC2 were rescued in these cells. A similar experimental strategy rescued the behavioral abnormalities in AD mice. We found 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 4a (HNF-4A) transcription factor, which disrupted its binding to the miR-101b promoter. The suppression of miR-101b caused an upregulation of its target, adenosine 5’-monophosphate (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.