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首页> 外文期刊>RSC Advances >HSA targets multiple A beta 42 species and inhibits the seeding-mediated aggregation and cytotoxicity of A beta 42 aggregates
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HSA targets multiple A beta 42 species and inhibits the seeding-mediated aggregation and cytotoxicity of A beta 42 aggregates

机译：HSA靶向多种β22种并抑制β22聚集体的播种介导的聚集和细胞毒性

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摘要

Human serum albumin (HSA) is an important binding partner of amyloid-beta (A beta) in vivo and it can modulate A beta aggregation. However, the underlying molecular mechanism of this HSA-mediated modulation of Ab aggregation and cytotoxicity is still not fully understood, especially that of A beta 42, which is the most amyloidogenic and toxic A beta variant. For this reason, we systematically investigated the effect of HSA on the fibrillation and cytotoxicity of different A beta 42 aggregation species in the amyloid-formation pathways by extensive biophysical and biological tests. Moreover, a Surface Plasmon Resonance (SPR) assay was performed to determine the ability of HSA to bind to different A beta 42 species. Collective results indicated several important findings as follows: (i) HSA inhibited the fibrillation of the A beta 42 monomer in a concentration-dependent manner; (ii) HSA abolished the seeding ability of protofibril and fibril at a 1 : 1 molar ratio; (iii) HSA interacted with A beta 42 protofibrils and fibrils with increased affinity and formed HSA-A beta complexes that dissociated at a slower rate than the complex formed between HSA and the A beta 42 monomer; (iv) HSA prevented seeding-mediated cytotoxicity of A beta 42. Taken together, these findings suggested that the HSA inhibited A beta 42 fibrillation and cytotoxicity through interfering with different stages of A beta 42 fibrillation and targeting different A beta 42 intermediate aggregates. Furthermore, HSA preferentially interacted with A beta fibrillar aggregates to form slowly-dissociated complexes. These findings contributed to a better understanding of the molecular mechanism by which HSA modulates the aggregation and cytotoxicity of A beta, and provide important implications for further designing HSA-based therapeutic strategies.
机译：人血清白蛋白（HSA）是体内淀粉样蛋白β（Aβ）的重要结合伴侣，它可以调节β聚集体。然而，该HSA介导的AB聚集和细胞毒性调节的潜在分子机制仍然不完全理解，尤其是β22的β22，其是最淀粉样蛋白和毒性的β变体。因此，我们通过广泛的生物物理和生物学试验系统地研究了HSA对淀粉样蛋白形成途径不同β22聚集物种的纤维化和细胞毒性的影响。此外，进行了表面等离子体共振（SPR）测定以确定HSA与不同β22种的能力结合。集体结果表明了以下几个重要发现如下：（i）HSA以浓度依赖性方式抑制β22单体的纤维化; （ii）HSA废除了原料纤维和原纤维的播种能力，1：1摩尔比; （iii）用β22种子纤维和原纤维与β220-原纤维相互作用，具有增加的亲和力和形成的HSA-Aβ配合物，其与在HSA和β22单体之间形成的复合物以较慢的速率分离; （iv）HSA预防播种介导的β22的细胞毒性。通过干扰β22纤维化的不同阶段和靶向不同的β22中间聚集体，通过干扰β22纤维化的不同阶段抑制β22纤维化和细胞毒性并靶向不同的β242中间聚集体，表明HSA抑制了β22纤维化和细胞毒性。此外，HSA优先与β纤维菌聚集体相互作用以形成缓慢解离的配合物。这些发现有助于更好地理解HSA调节β的聚集和细胞毒性的分子机制，并为进一步设计基于HSA的治疗策略提供重要意义。

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  • 来源
    《RSC Advances》 |2016年第75期|共11页
  • 作者

    Wang Conggang; Cheng Fang; Xu Li; Jia Lingyun;

  • 作者单位

    Dalian Univ Technol Sch Life Sci &

    Biotechnol Dalian 116023 Peoples R China;

    Dalian Univ Technol Sch Pharmaceut Sci &

    Technol Dalian 116023 Peoples R China;

    Dalian Univ Technol Sch Life Sci &

    Biotechnol Dalian 116023 Peoples R China;

    Dalian Univ Technol Sch Life Sci &

    Biotechnol Dalian 116023 Peoples R China;

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  • 正文语种 eng
  • 中图分类 化学;
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