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首页> 外文学位 >Putting the Brakes on Proliferation Gene Dosage Effects on Hippocampal Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome.
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Putting the Brakes on Proliferation Gene Dosage Effects on Hippocampal Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome.

机译：在唐氏综合症的Ts65Dn小鼠模型中放慢对增殖基因剂量对海马神经发生的影响。

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摘要

As the most prevalent genetic cause of intellectual disability in the western world, Down syndrome (DS) presents a variety of challenges. This is especially true for the aging DS population, which is facing the reality that virtually all individuals who survive to their fifth decade will develop Alzheimer's disease. Thus, it has become imperative to identify and understand underlying mechanisms that can potentially contribute to cognitive impairments in DS. Given that most of the cognitive deficits in DS have been associated with hippocampal dysfunction and that neurogenesis in the adult hippocampus contributes to cognitive processing, the goal of our research was to determine whether adult hippocampal neurogenesis is impaired in the hippocampi of a mouse model of DS, Ts65Dn. Results presented herein demonstrate that neurogenesis is significantly (∼50%) reduced in the subgranular zone (SGZ) of the dentate gyrus of adult male Ts65Dn mice. The use of the thymidine analog 5'-Bromo-2-deoxyuridine (BrdU) and cell-type specific markers led us to conclude that a significantly large proportion of the neuroprogenitor population resident within the SGZ fails to proliferate. The consequence of reduced cell proliferation is a significant deficit in the production of new neurons in the dentate gyrus, which may ultimately impinge upon hippocampal function. Gene overexpression in DS may contribute to cell cycle alterations within the neuroprogenitor population via dysregulation of signaling pathways required for neurogenesis and through the overproduction of reactive oxygen species (ROS), which negatively impact cell viability. Our research has established that chronic treatment with the antidepressant fluoxetine rescues impaired neurogenesis, increasing cell proliferation to control levels. Additionally, we have shown that treatment with the antioxidant curcumin can be neuroprotective through the reduction of oxidative damage, which in turn facilitates the generation of new neurons. Ultimately, we have identified a mechanism that can contribute to hippocampal dysfunction in DS and have established that dysregulation of neurogenesis can be remedied using pharmacological therapies already available, thus, providing hope for future treatments.
机译：唐氏综合症（DS）是西方世界最普遍的智力障碍遗传病因，带来了各种各样的挑战。对于DS人口老龄化尤其如此，它正面临着这样一个现实，即几乎所有存活至第五个十年的人都将患上阿尔茨海默氏病。因此，识别和理解可能导致DS认知障碍的潜在机制已变得势在必行。鉴于DS的大多数认知缺陷都与海马功能障碍有关，并且成年海马的神经发生有助于认知过程，因此我们的研究目标是确定DS小鼠模型的海马中是否损害了成年海马的神经发生。 ，Ts65Dn。本文提供的结果表明，成年雄性Ts65Dn小鼠的齿状回的亚颗粒区（SGZ）神经发生显着减少（〜50％）。胸苷类似物5'-Bromo-2-deoxyuridine（BrdU）和细胞类型的特异性标记的使用使我们得出结论：驻留在SGZ中的神经祖细胞群中有很大一部分无法增殖。减少细胞增殖的结果是在齿状回中新神经元的生产中明显缺乏，这可能最终影响海马功能。 DS中的基因过表达可能通过神经发生所需信号通路的失调和活性氧（ROS）的过量产生而导致神经祖细胞内的细胞周期改变，这会对细胞活力产生负面影响。我们的研究已经确定，抗抑郁药氟西汀的长期治疗可以挽救受损的神经发生，将细胞增殖提高至控制水平。此外，我们已经表明，使用抗氧化剂姜黄素可以通过减少氧化损伤来保护神经，从而促进新神经元的产生。最终，我们确定了可导致DS中海马功能障碍的机制，并确定可以使用已有的药理疗法来纠正神经发生的调节异常，从而为将来的治疗提供希望。

著录项

  • 作者

    Clark, Sarah M.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 162 p.
  • 总页数 162
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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