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Abeta affects apoE transcriptionally through the activation of beta-AR, cAMP and AP-2.

机译：Abeta通过激活β-AR，cAMP和AP-2转录影响apoE。

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摘要

Two key players in the development of Alzheimer's disease (AD) are amyloid beta protein (Abeta) and apolipoprotein E (apoE). We and others have reported that Abeta elevates apoE protein levels in astrocytes, which in turn could alter lipid trafficking and cell function. The mechanism for the Abeta-induced increase in apoE levels is not clearly understood. We propose that Abeta affects apoE transcriptionally through the activation of the beta-adrenergic receptor (betaAR), cAMP and the activator protein 2 (AP-2).;To test this hypothesis it was first determined if the stimulation of apoE protein levels by Abeta was triggered by an upregulation of apoE mRNA, in contrast to changes in secretion or degradation. The results show a time-dependent increase in apoE mRNA expression levels with peak expression reached after 1 hour of Abeta treatment. betaAR antagonists were used to evaluate the involvement of the betaAR. The antagonists significantly inhibited the Abeta-induced stimulation of apoE mRNA and protein levels.;In order to further understand the mechanism behind these results we assessed cAMP role in the proposed Abeta-apoE pathway. This second messenger has been associated with AD and has been shown to elevate apoE message and secretion levels. The data shows an Abeta-dependent elevation in cAMP levels as well as an increase in apoE levels after dBcAMP treatment, confirming the activation of a cAMP-dependent pathway. In addition, I provide evidence that confirms the participation of the transcription factor AP-2, specifically that of AP-2beta. AP-2 is known to be unregulated by cAMP and to bind to the apoE promoter. I report an increase in AP-2beta translocation to the nucleus after both cAMP and Abeta treatment and confirm its participation in the activation of the apoE promoter.;In conclusion, my work reveals a novel pathway for Abeta stimulation of apoE abundance in astrocytes involving betaAR and the transcription factor AP-2beta. These findings not only help clarify the relationship between Abeta and apoE but also help understand AD progression and possibly show a mechanism that could aid in the fight against this fast growing disease.
机译：阿尔茨海默氏病（AD）发展的两个关键因素是淀粉样β蛋白（Abeta）和载脂蛋白E（apoE）。我们和其他人已经报道，Abeta升高星形胶质细胞中apoE的蛋白水平，这反过来又可能改变脂质的运输和细胞功能。 Abeta诱导的apoE水平增加的机制尚不清楚。我们建议Abeta通过激活β-肾上腺素受体（betaAR），cAMP和激活蛋白2（AP-2）来影响apoE转录；为了验证这一假设，首先确定是否通过Abeta刺激apoE蛋白水平与分泌或降解的变化相反，apoE mRNA的上调触发了这种变化。结果显示apoE mRNA表达水平随时间增加，在Abeta处理1小时后达到峰值表达。 betaAR拮抗剂用于评估betaAR的参与。拮抗剂显着抑制了Abeta诱导的apoE mRNA和蛋白水平的刺激。为了进一步了解这些结果背后的机制，我们评估了cAMP在拟议的Abeta-apoE途径中的作用。这第二个信使已经与AD相关联，并显示出可以提高apoE消息和分泌水平。数据显示，经dBcAMP处理后，cAMP水平的Abeta依赖性升高以及apoE含量的增加，证实了cAMP依赖性途径的激活。此外，我提供的证据证实了转录因子AP-2（特别是AP-2beta）的参与。已知AP-2不受cAMP调控，并与apoE启动子结合。我报告了cAMP和Abeta治疗后AP-2beta向核的转运增加，并证实其参与了apoE启动子的激活。总之，我的工作揭示了Abeta刺激涉及betaAR的星形胶质细胞中apoE丰富的新途径。和转录因子AP-2beta。这些发现不仅有助于阐明Abeta和apoE之间的关系，而且还有助于了解AD进展，并可能显示出有助于对抗这种快速增长的疾病的机制。

著录项

  • 作者

    Rossello, Ximena Serenella.;

  • 作者单位

    University of Minnesota.;

  • 授予单位 University of Minnesota.;
  • 学科 Health Sciences Pharmacology.;Biology Neurobiology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 122 p.
  • 总页数 122
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

  • 入库时间 2022-08-17 11:38:25

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