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首页> 外文学位 >Glycoprotein Ib alpha: An intrinsic promoter of amyloid beta fibrillization.
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Glycoprotein Ib alpha: An intrinsic promoter of amyloid beta fibrillization.

机译：糖蛋白Ibα：淀粉样β原纤维化的内在启动子。

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摘要

A predominant modern theory links Alzheimer's disease (AD)-related neurotoxicity to early-stage amyloid beta (Aβ) oligomers rather than mature Aβ fibers and plaques. It is believed that the process of Aβ fibrillization dictates Aβ toxicity, and that in vivo cofactors which mediate the kinetics of Aβ aggregation play a critical role in AD pathogenesis. As a potential modulator of Aβ aggregation, the effects of platelet surface receptor glycoprotein Ib alpha (GPIbα) on Aβ fibrillization were investigated. Time course thioflavin-T (ThT) fluorometry demonstrated that GPIb2V—a fully-sulfated GPIbα variant with platelet-type von Willebrand disease (Pt-vWD) mutations—dramatically enhanced Aβ fibrillization. Subsequent ThT studies indicated that the Pt-vWD mutations instigated Aβ aggregation, implying an interaction similar to that between GPIb2V and von Willebrand Factor (vWF). Bis-ANS fluorometry and far-UV circular dichroism showed that GPIb2V reduced the duration of Aβ oligomerization. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and size exclusion chromatography (SEC) demonstrated that Aβ aggregates and low molecular mass Aβ respectively appear and disappear more rapidly in the presence of GPIb2V, and that the latter co-aggregates with Aβ. Multiangle laser light scattering (MALLS) confirmed that Aβ aggregates observed on SEC were fibrillar in nature. A preliminary cell-based cytotoxicity assay suggested that GPIb2V alleviated Aβ neurotoxicity. These results revealed a potential link between this intrinsic "cardiovascular" protein and AD pathology.
机译：现代的一个主流理论将阿尔茨海默氏病（AD）相关的神经毒性与早期淀粉样β（Aβ）低聚物联系起来，而不是与成熟的Aβ纤维和斑块联系起来。认为Aβ原纤维化的过程决定了Aβ毒性，介导Aβ聚集动力学的体内辅因子在AD发病机理中起关键作用。作为Aβ聚集的潜在调节剂，研究了血小板表面受体糖蛋白Ibα（GPIbα）对Aβ原纤维化的影响。时程硫代黄素-T（ThT）荧光测定法表明，GPIb2V是一种完全硫酸化的GPIbα变异体，具有血小板型von Willebrand病（Pt-vWD）突变，可显着增强Aβ纤维化。随后的ThT研究表明，Pt-vWD突变促使Aβ聚集，这暗示了类似于GPIb2V和von Willebrand Factor（vWF）之间的相互作用。 Bis-ANS荧光法和远紫外圆二色性表明GPIb2V减少了Aβ寡聚化的持续时间。十二烷基硫酸钠聚丙烯酰胺凝胶电泳（SDS-PAGE）和尺寸排阻色谱（SEC）表明，在存在GPIb2V的情况下，Aβ聚集体和低分子量Aβ分别出现和消失得更快，并且后者与Aβ共聚集。多角度激光散射（MALLS）证实，在SEC上观察到的Aβ聚集体本质上是原纤维。初步的基于细胞的细胞毒性测定表明，GPIb2V减轻了Aβ神经毒性。这些结果揭示了这种内在的“心血管”蛋白与AD病理之间的潜在联系。

著录项

  • 作者

    Carter, Tyler L.;

  • 作者单位

    University of Massachusetts Lowell.;

  • 授予单位 University of Massachusetts Lowell.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 101 p.
  • 总页数 101
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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