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.
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DOI：
10.1016/j.jbc.2022.101794
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Zhang S;Bai P;Lei D;Liang Y;Zhen S;Bakiasi G;Pang H;Choi SH;Wang C;Tanzi RE;Zhang C
表观遗传调控在人类病理生理学中发挥着重要作用，这为通过靶向表观遗传途径干预人类疾病提供了机会。最近，来自临床前研究的新证据表明，通过靶向溴域包含蛋白4(BRD4)，一种表观遗传调节蛋白，有可能开发治疗阿尔茨海默病(AD)的方法。然而，迫切需要对AD相关的病理事件进行进一步的表征。在这里，我们研究了药物降解或抑制BRD4对AD细胞模型的影响。有趣的是，我们发现ARV825和JQ1分别对BRD4的降解和抑制都显著增加了淀粉样β蛋白(Aβ)的水平，这与AD的神经病理有关。随后，我们描述了下调BRD4增加Aβ水平的机制。我们发现，BRD4的降解和抑制都增加了BACE1的水平，BACE1是负责裂解淀粉样β蛋白前体(APP)生成Aβ的酶。与β增加一致的是，我们还发现，在我们的3D-AD人类神经细胞培养模型中，下调BRD4增加了AD相关的磷酸化Tau(PTAU)蛋白。因此，我们的结果表明，下调BRD4不是AD干预的可行策略。总之，我们的研究不仅表明BRD4是一个新的表观遗传学成分，调节BACE1和Aβ水平，而且还为BRD4的潜在临床应用靶向提供了新的翻译见解。
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.
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影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
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影响因子：
16.6
作者：
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4.2
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影响因子：
6.2
作者：
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通讯作者：
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影响因子：
15.1
作者：
Zhang C;Khandelwal PJ;Chakraborty R;Cuellar TL;Sarangi S;Patel SA;Cosentino CP;O'Connor M;Lee JC;Tanzi RE;Saunders AJ
通讯作者：
Saunders AJ