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 etiology and effective treatments requires to be discovered. The neuropathology of AD has been well characterized by two hallmarks in AD brains. They include the extracellular amyloid plaques, which are primarily formed by deposition of the β-amyloid (Aβ) peptides, which is usually early pathological manifestations of AD, and the intraneuronal neurofibrillary tangles within the dystrophic neurites, which consist of the aggregated and pathologic Tau proteins, and usually occurs in later stages of AD following Aβ accumulation (3Serrano-Pozo A. Frosch M.P. Masliah E. Hyman B.T. Neuropathological alterations in Alzheimer disease.Cold Spring Harb. Perspect. Med. 2011; 1: a006189Crossref PubMed Scopus (1728) Google Scholar). Although the pathogenesis of AD is complex and has not been completely elucidated, investigation of disease neuropathology has led to considerable evidence supporting “Aβ hypothesis.” It posits that Aβ upregulation and accumulation are the primary pathological events of AD, which induce phosphorylated Tau (pTau) in neurons, followed by neurofibrillary tangle formation and neuroinflammation, as well as synaptic dysfunction and loss, and ultimately, neurodegeneration (4Hardy J. Selkoe D.J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics.Science. 2002; 297: 353-356Crossref PubMed Scopus (10549) Google Scholar, 5Bertram L. Tanzi R.E. Thirty years of Alzheimer’s disease genetics: The implications of systematic meta-analyses.Nat. Rev. Neurosci. 2008; 9: 768-778Crossref PubMed Scopus (592) Google Scholar, The of amyloid accumulation in common of Alzheimer Google Scholar, C. C. B. C. J. C. D.M. et human neural cell culture of Alzheimer’s PubMed Scopus Google Scholar). Recently, has been on the of AD pathogenesis as well as targeting for developing therapeutics of AD L. J.L. T. A. Epigenetic of in is associated with Alzheimer’s disease and 2019; PubMed Scopus Google Scholar, A. A. as in Alzheimer’s disease 2019; 14: PubMed Scopus Google Scholar). Epigenetic and to and L. J.L. T. A. Epigenetic of in is associated with Alzheimer’s disease and 2019; PubMed Scopus Google Scholar). The pathogenesis for AD and complex epigenetic mechanisms A. A. F. C. of the epigenetic of in Alzheimer’s Neurosci. 2018; PubMed Scopus Google Scholar, Alzheimer disease: with Alzheimer Rev. 2018; 14: PubMed Scopus Google Scholar). Therefore, and of mechanisms by which epigenetic to AD pathological novel insights of AD etiology and generate with for AD protein 4 is a of epigenetic regulation which has been for both biological and clinical a that to the bromodomain and protein BRD4 as an epigenetic with roles in regulation E. of bromodomain and for human Rev. PubMed Google Scholar, to to and cell 2008; PubMed Scopus Google Scholar, K. K. The bromodomain protein is a regulatory component of and Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. J. and of the bromodomain of with 2008; PubMed Scopus Google Scholar). to the the and to BRD4 is well characterized for a to to and cell 2008; PubMed Scopus Google Scholar, K. K. The bromodomain protein is a regulatory component of and Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. J. and of the bromodomain of with 2008; PubMed Scopus Google Scholar, A. in the of cell and Full Text Full Text PDF PubMed Scopus Google Scholar). It also with the and to E. of bromodomain and for human Rev. PubMed Google Scholar). BRD4 an component of a A. in the of cell and Full Text Full Text PDF PubMed Scopus Google Scholar). to as a BRD4 is a of by with the D.J. BRD4 is a characterized that and PubMed Scopus Google Scholar, J. W. A. C. T. protein BRD4 is a of and Full Text Full Text PDF PubMed Scopus Google which regulates BRD4 is to cell in BRD4 are to and on levels to to and cell 2008; PubMed Scopus Google Scholar). in BRD4 J. A. A. E. A. BRD4 with and BRD4 is in a 2018; PubMed Scopus Google Scholar, J. W. of a novel in BRD4 that causes associated with Scholar, J. J. et with a a of 2019; PubMed Scopus Google Scholar). BRD4 is to and regulation to and E. protein in and in Neurosci. PubMed Scopus Google Scholar). Because BRD4 is a that human pathophysiology, has an for clinical as and targeting been and in clinical J. and of bromodomain and for the treatment of and systematic study of clinical PubMed Scopus Google Scholar, C. A. A. A. of targeting in 2019; PubMed Scopus Google Scholar, A. A. are for of the cell in J. 2019; Scopus Google Scholar, K. J. et targeting of BRD4 2019; PubMed Scopus Google Scholar, C. E. effects of targeting for degradation with in to 2019; PubMed Scopus Google Scholar). clinical in to BRD4 has been suggested to be a in and from preclinical studies A. A. are for of the cell in J. 2019; Scopus Google Scholar, K. J. et targeting of BRD4 2019; PubMed Scopus Google Scholar). preclinical evidence suggested that BRD4 be a potential for AD intervention. is a that is a of J. T. et inhibition of PubMed Scopus Google Scholar, L. J. J. of PubMed Scopus Google Scholar). It has been on the pathological and levels. the pathological levels, levels in the AD C. The and in the of the of Alzheimer’s Alzheimer PubMed Scopus Google Scholar). also regulates and J. J. B. W. BRD4 inhibition in and in Med. 2019; PubMed Scopus Google Scholar, W. C. Liu 2018; PubMed Scopus Google Scholar, A. mechanisms of the of PubMed Scopus Google Scholar). with effects on E. B. C. A. The in and PubMed Scopus Google but shows effects on and AD-related studies in a study E. protein in and in Neurosci. PubMed Scopus Google Scholar). E. B. C. A. The in and PubMed Scopus Google Scholar). suggest that BRD4 protein plays complex and in of AD. the effects of BRD4 on Aβ and further Here, our study has been to on the effects of pharmacological regulation of BRD4 on AD cell both degradation and inhibition We that our study novel and translational insights in clinical to AD. this we to the and to pharmacological regulation of Recently, of been and clinical We for clinical which led to of of for We two that or proteins, They a for J. J. K. J. K. the to Full Text Full Text PDF PubMed Scopus Google and for J. T. et inhibition of PubMed Scopus Google ARV-825 is to a in a has been investigated in preclinical studies and provides an effective and to study the of not to clinical to A. K. D.M. A. T. J. and of preclinical and clinical in 2019; PubMed Scopus Google Scholar). our we investigated the effects of ARV-825 on Aβ levels and in the human a cell with ARV-825 of and for to to Aβ levels. and to to We found that the and the also by results that the treatment of We in cell to and BRD4 protein levels and in to Aβ levels. We that ARV-825 BRD4 protein levels, as and to BRD4 degradation and also with J. J. K. J. K. the to Full Text Full Text PDF PubMed Scopus Google Scholar). 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The in and PubMed Scopus Google Scholar). we investigated the effects of ARV-825 or on component levels by an for the we that ARV-825 or not levels with and we the effects of ARV-825 or on a which is for and K. C. T. as a Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, in ARV-825 the of ARV-825 levels to and levels to and levels to and ARV-825 or increased Aβ levels by mechanisms primarily an upregulation of BACE1 levels and but not by levels and AD-related Aβ in BACE1 J. B. T. E. L. amyloid precursor protein enzyme levels in amyloid for Alzheimer’s disease Neurosci. PubMed Scopus Google we BACE1 upregulation by ARV-825 and also in we which Aβ levels. The for with ARV-825 and JQ1, the of which that effects on Aβ levels and in The cell and to and and we found that ARV-825 or increased BACE1 levels, respectively, with and ARV-825 or levels, respectively, with We also the effects of ARV-825 or on levels. 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D.M. et human neural cell culture of Alzheimer’s PubMed Scopus Google to study AD-related Tau protein the human neural the and and the and to and with and or for The and by to and We found that increased levels of BACE1 and and with levels to Aβ levels from and Aβ levels from by We that or not Aβ levels in the of levels in in with and with The of the to which the of both Tau and phosphorylated Tau We that and increased levels with the to an to and led to increases of with associated with an to we to and found that but led to an of levels and Because Tau in our 3D-AD culture is on and amyloid C. C. B. C. J. C. 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We also or ARV-825 on The with ARV-825 or for and and by We that and ARV-825 but increased with and our results suggested a of BACE1 and Aβ levels of our results with that BRD4 downregulation is to D.J. BRD4 is a characterized that and PubMed Scopus Google Scholar). study the effects and translational of targeting an epigenetic on AD cell of AD. has been in targeting BRD4 in clinical which has led to as and for in this and component of are both of that primarily BRD4 J. T. et inhibition of PubMed Scopus Google Scholar, J. J. K. J. K. the to Full Text Full Text PDF PubMed Scopus Google Scholar). Recently, preclinical evidence BRD4 with translational we studies by inhibition of BRD4 by or degradation of BRD4 by The and of our study are in the following our results effects of both degradation and inhibition of BRD4 on Aβ and in cell models. The amyloid hypothesis of AD the of AD characterized by Aβ and Tau (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, C. C. B. C. J. C. D.M. et human neural cell culture of Alzheimer’s PubMed Scopus Google Scholar). Aβ or the occurs through the which and regulation of BACE1 protein and 2019; PubMed Scopus Google Scholar, C. Tanzi R.E. The and of and as in the of Alzheimer’s disease: PubMed Scopus Google Scholar). with followed by cleavage to Aβ. to Aβ increase, we the human neural cell of AD to study AD-related C. C. B. C. J. C. D.M. et human neural cell culture of Alzheimer’s PubMed Scopus Google Scholar). We an upregulation of increased Tau protein and increased BACE1 levels as a of BRD4 inhibition in our 3D-AD human neural culture model. Collectively, our results the amyloid hypothesis and suggested an of BRD4 downregulation with amyloid and in AD cell models. the clinical potential of targeting BRD4 for AD, our results in this study not an in AD. has been investigated to potential as an AD study has insights in this with effects on in and in AD E. B. C. A. The in and PubMed Scopus Google shows effects on and in in a study E. protein in and in Neurosci. PubMed Scopus Google Scholar). The of be by the in two and that levels in the of AD C. The and in the of the of Alzheimer’s Alzheimer PubMed Scopus Google Scholar). from our study characterized AD-related Aβ levels and in as well as Tau in our 3D-AD human neural culture model. we found increased Tau for both protein and protein in our 3D-AD neural culture We that our from by and which be to and in models. we 3D-AD human neural culture in and Tau the AD Tau a Tau that not in AD. not only we an of Aβ but we also increased BACE1 levels in with ARV-825 or of BACE1 and been investigated for mechanisms in with AD K. An to PubMed Scopus Google Scholar). studies that an in BACE1 neurodegeneration in E. A. L. L. L. Masliah E. The of amyloid precursor protein and and Full Text Full Text PDF PubMed Scopus Google and and L. A. A. F. J. C. K. C. C. et neurodegeneration in in amyloid-beta for the treatment of Alzheimer PubMed Google Scholar). BACE1 has of which is to cleavage of the and BACE1 in K. K. A. B. of amyloid precursor protein and in Alzheimer’s disease and human PubMed Scopus Google Scholar, A. E. B. J.M. C. S.B. F. human BACE1 in 2018; 9: PubMed Scopus Google Scholar). Although not for AD, BRD4 has been in Because BRD4 with is to of and the downregulation of BRD4 to cell and to to and cell 2008; PubMed Scopus Google Scholar). inhibition is a potential in and has also been in as and in of J. and of bromodomain and for the treatment of and systematic study of clinical PubMed Scopus Google Scholar, C. A. A. A. of targeting in 2019; PubMed Scopus Google Scholar, A. A. are for of the cell in J. 2019; Scopus Google Scholar, K. J. et targeting of BRD4 2019; PubMed Scopus Google Scholar, C. E. effects of targeting for degradation with in to 2019; PubMed Scopus Google Scholar). our study has of BRD4 on AD-related and is the to our which and levels be by epigenetic regulation of bromodomain protein in with studies that is a that BACE1 levels by T. C. The BACE1 regulates the of in the Full Text Full Text PDF PubMed Scopus Google Scholar). We an upregulation of as a of BRD4 downregulation by and which associated with increased BACE1 levels. We also that the of BACE1 on a our results that BACE1 levels not as a of BRD4 we that not by BRD4 the levels of Interestingly, we found that BRD4 downregulation by both and ARV-825 levels, BRD4 as a that the of the of our study and suggest complex mechanisms regulation of the events of AD. we a by which and inhibition or degradation of BRD4 increases Aβ levels through BACE1 and in AD cell models. study by et E. B. C. A. The in and PubMed Scopus Google on by in both AD and The found that the for and not in AD E. B. C. A. The in and PubMed Scopus Google Scholar). the that in as a of not include and BACE1, and E. B. C. A. The in and PubMed Scopus Google Scholar). results further a of of BACE1 and proteins, with our It that BRD4 BACE1 or on levels, which BACE1 and levels. The by which BRD4 BACE1 and in our AD with cell and or J. W. A. C. T. protein BRD4 is a of and Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. et regulates BACE1 and in Alzheimer’s A. 2019; PubMed Scopus Google Scholar, of of PubMed Scopus Google which Interestingly, an BRD4 and regulates the and A. K. J. L. L. C. C. W. J. et of is a for in PubMed Scopus Google Scholar, W. A. W. regulation of BACE1, the precursor protein by PubMed Scopus Google which been to the of and BACE1 in AD amyloid precursor protein degradation and of 14: PubMed Scopus Google Scholar, B. K. A. B. and of and and to Alzheimer’s 2008; PubMed Scopus Google Scholar). results complex for the regulatory of BRD4 in It is with that BRD4 both and for regulation of of of PubMed Scopus Google with effects on E. protein in and in Neurosci. PubMed Scopus Google Scholar, E. B. C. A. The in and PubMed Scopus Google Scholar). the results of our study and studies a which shows that inhibition or degradation of increases in AD that BRD4 with and in upregulation of for cell and to to and cell 2008; PubMed Scopus Google Scholar, K. K. The bromodomain protein is a regulatory component of and Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. J. and of the bromodomain of with 2008; PubMed Scopus Google Scholar). The the of BRD4 and BRD4 from the inhibition or degradation of to and BRD4 with and the and protein evidence also that targeting BRD4 regulation of and D.J. BRD4 is a characterized that and PubMed Scopus Google Scholar). BRD4 with the and the which of by of D.J. BRD4 is a characterized that and PubMed Scopus Google Scholar, J. W. A. C. T. protein BRD4 is a of and Full Text Full Text PDF PubMed Scopus Google Scholar). Here, we evidence that Aβ levels a by which increases BACE1 protein levels through a BACE1 and of with as a of BRD4 downregulation by results complex mechanisms in regulation of BRD4 and insights in targeting BRD4 our study has novel and translational insights for targeting BRD4 in AD clinical applications. We that pharmacological degradation and inhibition of BRD4 increased Aβ levels that are to AD neuropathology in cell models. clinical our results suggest that downregulation of BRD4 not be a strategy for AD. ARV-825 and JQ1, from and and in The to and targeting of by and C. Tanzi R.E. A. the degradation of novel PubMed Scopus Google Scholar, J. Tanzi R.E. C. that of and protein to pathogenesis and treatment of Alzheimer’s Med. Google Scholar, C. J. B. A. Tanzi R.E. Liu K. C. upregulation of Alzheimer’s levels in a by extracellular 2019; PubMed Scopus Google Scholar). 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An to PubMed Scopus Google Scholar). in containing The and 4 for The and the to a protein the protein the with the for The for The to Aβ levels by further with and 4 for The with and to by the J. Tanzi R.E. C. that of and protein to pathogenesis and treatment of Alzheimer’s Med. Google Scholar, C. A. Tanzi R.E. of of increases amyloid levels by of precursor Full Text Full Text PDF PubMed Scopus Google Scholar, C. Tanzi R.E. An to PubMed Scopus Google Scholar). protein and to the followed by and The as an The with to the and the of to J. Tanzi R.E. C. that of and protein to pathogenesis and treatment of Alzheimer’s Med. Google Scholar, C. A. Tanzi R.E. of of increases amyloid levels by of precursor Full Text Full Text PDF PubMed Scopus Google Scholar, C. Tanzi R.E. An to PubMed Scopus Google Scholar). The to cell and and has been C. A. 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C. of Alzheimer’s disease amyloid-beta protein precursor in both in and in Alzheimer’s PubMed Scopus Google Scholar). proteins, the and and and phosphorylated the the with with for the and the protein and on a 4 followed by and the Subsequently, the by the levels of the on the protein levels from the treatment and to from the The and in culture as with JQ1, or ARV-825 The with for and by with a containing for with containing with primary and BACE1 from in the 4 with the with for the with in to the cell for The with a of on of the The the of the following C. A. Tanzi R.E. of of increases amyloid levels by of precursor Full Text Full Text PDF PubMed Scopus Google and suggested a and in a containing of and and The as followed by of to the suggested on a The that the a the the and a to by the 2008; PubMed Scopus Google Scholar). for BACE1, and A. J. E. L. regulates cell and in and in A. PubMed Scopus Google Scholar, regulation of BACE1 by and 2011; PubMed Scopus Google Scholar, A. A. F. A. is by alterations of in and PubMed Scopus Google and for from The for two The followed by for of two in to the The results as to be the are within the supporting to to and cell 2008; PubMed Scopus Google Scholar, K. K. The bromodomain protein is a regulatory component of and Full Text Full Text PDF PubMed Scopus Google Scholar, J. B. J. and of the bromodomain of with 2008; PubMed Scopus Google Scholar, D.J. BRD4 is a characterized that and PubMed Scopus Google Scholar). The that of with the of this by the and the Alzheimer’s C. E. and C. and C. E. and C. C. E. and C. and

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