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  3. Degradation and inhibition of epigenetic regulatory protein BRD4 exacerbate Alzheimer's disease-related neuropathology in cell models

Degradation and inhibition of epigenetic regulatory protein BRD4 exacerbate Alzheimer's disease-related neuropathology in cell models

  • J Biol Chem. 2022 Apr;298(4):101794. doi: 10.1016/j.jbc.2022.101794.
Siyi Zhang 1,  Ping Bai 2,  Dan Lei 3,  Yingxia Liang 3,  Sherri Zhen 3,  Grisilda Bakiasi 3,  Hao Pang 4,  Se Hoon Choi 3,  Changning Wang 5,  Rudolph E Tanzi 3,  Can Zhang 6
Affiliations

Affiliations

  • 1 Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA; Department of Forensic Medicine, China Medical University, Shenyang, China.
  • 2 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
  • 3 Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
  • 4 Department of Forensic Medicine, China Medical University, Shenyang, China.
  • 5 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. Electronic address: CWANG15@mgh.harvard.edu.
  • 6 Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. Electronic address: Zhang.Can@mgh.harvard.edu.
PMID: 35248531 DOI: 10.1016/j.jbc.2022.101794
Abstract

Epigenetic regulation plays substantial roles in human pathophysiology, which provides opportunities for intervention in human disorders through the targeting of epigenetic pathways. Recently, emerging evidence from preclinical studies suggested the potential in developing therapeutics of Alzheimer's disease (AD) by targeting bromodomain containing protein 4 (BRD4), an epigenetic regulatory protein. However, further characterization of AD-related pathological events is urgently required. Here, we investigated the effects of pharmacological degradation or inhibition of BRD4 on AD cell models. Interestingly, we found that both degradation and inhibition of BRD4 by ARV-825 and JQ1, respectively, robustly increased the levels of amyloid-beta (Aβ), which has been associated with the neuropathology of AD. Subsequently, we characterized the mechanisms by which downregulation of BRD4 increases Aβ levels. We found that both degradation and inhibition of BRD4 increased the levels of BACE1, the Enzyme responsible for cleavage of the amyloid-beta protein precursor (APP) to generate Aβ. Consistent with Aβ increase, we also found that downregulation of BRD4 increased AD-related phosphorylated Tau (pTau) protein in our 3D-AD human neural Cell Culture model. Therefore, our results suggest that downregulation of BRD4 would not be a viable strategy for AD intervention. Collectively, our study not only shows that BRD4 is a novel epigenetic component that regulates BACE1 and Aβ levels, but also provides novel and translational insights into the targeting of BRD4 for potential clinical applications.

Keywords

Alzheimer’s disease; BACE1; amyloid-β; amyloid-β protein precursor; amyloidogenesis; bromodomain-containing protein 4; epigenetics; nicastrin; tau.

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