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 memoryrelated 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 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, 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.

Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer’s disease via C/EBPα/miR‐125b pathway

“…Next, we examined the exact underlying mechanisms of MT2’s protective effects against Aβ42‐induced dendritic injuries. Recently, the roles of microRNAs (miRNAs) in synaptic disorder observed in AD have been well elucidated (Li et al, ; Liu et al, ; Wang et al, ). Therefore, we then measured the expression of brain‐enriched miRNAs that had been reported previously upon the different treatments above.…”

“…Sholl analysis was used to measure dendritic complexity as reported previously (Liu et al, ; Serita, Fukushima, & Kida, ). It was conducted and analyzed using the semi‐automatized Imaris software (Bitplane, Inc).…”

“…The isolated embryonic hippocampal neurons (E18) were cultured as previously described (Liu et al, ). Briefly, the collected hippocampi were digested with 4 ml of 0.25% trypsin in D‐Hanks for 15 min and the digestion was stopped by adding at least 4 ml of the neuronal planting medium (10% fetal bovine serum in DMEM/F12).…”

Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain’s Reward Circuitry

“…As in the Patterns, CREB1 was a predicted upstream regulator in PFC, NAc, BLA, and vHIP of genes associated with AI (Figure 5J). HNF4A was also a predicted upstream regulator of genes associated with AI and was one of two upstream regulators (TCF7L2) predicted for both Patterns B and C. HNF4A is implicated in epigenetic mechanisms (49–52) and dendritic spine morphology (51). While expression of Hnf4a was not detected in our sequencing data, other NRs were.…”

Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer’s Disease in vitro Model

“…The HDAC2 deacetylates histone substrates at the promoter area of numerous synaptic-plasticity-associated genes (Guan et al, 2009;Gräff et al, 2012). Notably, both AD patient brains and multiple mouse models of AD have elevated levels of HDAC2 (Gonzalez-Zuñiga et al, 2014;Liu et al, 2017). Mithramycin A (MTM) is a gene selective specificity protein 1 (Sp1) inhibitor that is employed as a chemotherapeutic agent that inhibits tumor cell growth without affecting normal cells (Torrance et al, 2001).…”