Small molecule-mediated co-assembly of amyloid-β oligomers reduces neurotoxicity through promoting non-fibrillar aggregation,Chemical Science

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Small molecule-mediated co-assembly of amyloid-β oligomers reduces neurotoxicity through promoting non-fibrillar aggregation
Chemical Science ( IF 7.6 ) Pub Date : 2020-06-22 , DOI: 10.1039/d0sc00392a
Hao Liu _{1,

2,

3,

4} , Chengyuan Qian _{1,

2,

3,

4} , Tao Yang _{4,

5,

6,

7,

8} , Yanqing Wang _{4,

9,

10,

11} , Jian Luo _{1,

2,

3,

4} , Changli Zhang _{4,

12,

13,

14} , Xiaohui Wang _{1,

2,

3,

4,

15} , Xiaoyong Wang _{4,

5,

6,

7,

8} , Zijian Guo _{4,

7,

8,

15}

Affiliation

Amyloid-β (Aβ) oligomers, particularly low molecular weight (LMW) oligomers, rather than fibrils, contribute very significantly to the onset and progression of Alzheimer's Disease (AD). However, due to the inherent heterogeneity and metastability of oligomers, most of the conventional anti-oligomer therapies have indirectly modulated oligomers' toxicity through manipulating Aβ self-assembly to reduce oligomer levels, which are prone to suffering from the risk of regenerating toxic oligomers from the products of modulation. To circumvent this disadvantage, we demonstrate, for the first time, rational design of rigid pincer-like scaffold-based small molecules with blood–brain barrier permeability that specifically co-assemble with LMW Aβ oligomers through directly binding to the exposed hydrophobic regions of oligomers to form non-fibrillar, degradable, non-toxic co-aggregates. As a proof of concept, treatment with a europium complex (EC) in such a structural mode can rescue Aβ-mediated dysfunction in C. elegans models of AD in vivo. This small molecule-mediated oligomer co-assembly strategy offers an efficient approach for AD treatment.

中文翻译：

小分子介导的β-淀粉样蛋白低聚物的共组装可通过促进非纤维状聚集而降低神经毒性

淀粉样蛋白-β（Aβ）低聚物，特别是低分子量（LMW）低聚物，而不是原纤维，对阿尔茨海默氏病（AD）的发作和进展做出了非常重要的贡献。然而，由于低聚物固有的异质性和亚稳定性，大多数常规抗低聚物疗法已通过操纵Aβ自组装以降低低聚物水平来间接调节低聚物的毒性，这易于遭受从中再生有毒低聚物的风险。调制的产物。为了克服这个缺点，我们首次展示了具有血脑屏障通透性的刚性钳状支架基小分子的合理设计，该小分子通过与低分子量Aβ低聚物直接结合而直接与低聚物暴露的疏水区结合在一起形成非原纤维，可降解的无毒共聚集体。作为概念的证明，用这种结构模式的complex络合物（EC）治疗可以挽救Aβ介导的功能障碍。C.线虫模型的体内AD 。这种小分子介导的低聚物共组装策略为AD治疗提供了一种有效的方法。

更新日期：2020-07-15

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