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首页> 外文期刊>Cell death discovery. >Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment
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Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

机译：通过促进KHDRBS2转录通过在Aβ1-42微环境中募集KHDRBS2转录，伪影型ACTBP2通过募集KMT2D / WDR5来增加血脑屏障渗透性

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The blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48?h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.
机译：血脑屏障（BBB）在维持中枢神经系统（CNS）的稳态方面具有至关重要的作用。 BBB的结构和功能的变化可以加速阿尔茨海默病（AD）发展。 β-淀粉样（Aβ）沉积是广告的主要病理事件。我们阐述了假基因ACTBP2对Aβ1-42微环境中BBB渗透性作用的作用及可能的分子机制。用Aβ1-42处理的BBB模型48〜H用于模拟AD中的Aβ介导的BBB功能障碍。我们证明假基因actBP2，RNA结合蛋白KHDRBS2和转录因子Hey2在Aβ1-42微环境中的BBB模型中获得的ECS中高度表达。在Aβ1-42 - 培养的ECS中，ACTBP2促进甲基转移酶KMT2D和WDR5，与KHDRBS2启动子结合，并促进KHDRBS2转录。 KHDRBS2与Hey2 mRNA的3'UTR的相互作用增加了Hey2的稳定性并促进其表达。 Hey2通过转录抑制ZO-1，occludin和Claudin-5的表达，增加Aβ1-42微环境中的BBB渗透性。我们确认敲击KHDRBS2或Hey2增加了APP / PS1小鼠脑微血管中的ZO-1，Occludin和Claudin-5的表达水平。 ACTBP2 / KHDRBS2 / HEY2轴在Aβ1-42微环境中的BBB渗透性调节方面具有至关重要的作用，这可以为AD的治疗提供新的靶标。

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