{"doi":"10.1016/j.jbc.2022.101794","title":"Degradation and inhibition of epigenetic regulatory protein BRD4 exacerbate Alzheimer’s disease-related neuropathology in cell models","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. 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. Alzheimer’s disease (AD) is the most common cause of dementia, which tremendously causes worldwide financial loss and leads to severe social burden (1Long J.M. Holtzman D.M. Alzheimer disease: An update on pathobiology and treatment strategies.Cell. 2019; 179: 312-339Abstract Full Text Full Text PDF PubMed Scopus (670) Google Scholar, 2Jack Jr., C.R. Bennett D.A. Blennow K. Carrillo M.C. Dunn B. Haeberlein S.B. Holtzman D.M. Jagust W. Jessen F. Karlawish J. Liu E. Molinuevo J.L. Montine T. Phelps C. Rankin K.P. et al.NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease.Alzheimers Dement. 2018; 14: 535-562Abstract Full Text Full Text PDF PubMed Scopus (2976) Google Scholar). Because of the urgency of this situation, a better understanding of AD etiolo","journal":"Journal of Biological Chemistry","year":2022,"id":251675,"datarank":0.48283137373023016,"base_score":3.2188758248682006,"endowment":3.2188758248682006,"self_citation_contribution":0.48283137373023016,"citation_network_contribution":0.0,"self_endowment_contribution":0.48283137373023016,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":329735,"name":"Ping Bai","orcid":"0000-0003-4587-8426","position":1,"is_corresponding":false},{"id":895104,"name":"Dan Lei","orcid":"0000-0001-6944-1873","position":2,"is_corresponding":false},{"id":484434,"name":"Yingxia Liang","orcid":"0000-0003-3090-5815","position":3,"is_corresponding":false},{"id":638858,"name":"Sherri Zhen","orcid":"0000-0001-7263-9223","position":4,"is_corresponding":false},{"id":895602,"name":"Grisilda Bakiasi","orcid":null,"position":5,"is_corresponding":false},{"id":895105,"name":"Hao Pang","orcid":"0000-0002-6606-6438","position":6,"is_corresponding":false},{"id":260531,"name":"Se Hoon Choi","orcid":"0000-0002-7905-4380","position":7,"is_corresponding":false},{"id":329739,"name":"Changning Wang","orcid":"0000-0002-2076-4193","position":8,"is_corresponding":false},{"id":226532,"name":"Rudolph E. Tanzi","orcid":"0000-0002-7032-1454","position":9,"is_corresponding":false},{"id":270760,"name":"Can Zhang","orcid":"0000-0002-4340-5118","position":10,"is_corresponding":false},{"id":895103,"name":"Siyi Zhang","orcid":"0000-0001-8669-5285","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:24:41.993282Z","pmid":"35248531","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}