Different Inhibitors of Aβ42-Induced Toxicity Have Distinct Metal-Ion Dependency.
Different Inhibitors of Aβ42-Induced Toxicity Have Distinct Metal-Ion Dependency.
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DOI：
10.1021/acschemneuro.0c00192
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发表时间：
2020-08-05
影响因子：
5
通讯作者：
Bitan G
中科院分区：
文献类型：
--
作者：
Mason AJ;Hurst I;Malik R;Siddique I;Solomonov I;Sagi I;Klärner FG;Schrader T;Bitan G
β-淀粉样蛋白 (Aβ) 寡聚物被认为是引发阿尔茨海默病 (AD) 神经病理过程的近端毒性物质。因此，针对 Aβ 的自组装和寡聚化一直是设计 AD 疗法的重要策略。与此同时，AD 金属生物学研究表明，Zn2+ 可以在体外强烈调节 Aβ 的聚集，并根据实验条件促进和抑制 Aβ 的神经毒性。因此，成功的 Aβ 自组装抑制剂可能不仅要抑制 Aβ 寡聚物本身的毒性，还要抑制 Aβ-Zn2+ 复合物的毒性。然而，研究 Aβ 自组装和毒性抑制剂在 Zn2+ 存在下的影响的研究相对较少。我们的小组之前已经表征了一系列 Aβ42 C 末端片段 (CTF)，其中一些已被证明可以抑制 Aβ 寡聚化和神经毒性。在这里，我们询问三种被证明是 Aβ42 毒性的有效抑制剂的 CTF 在 Zn2+ 存在的情况下是否保持其活性。生物物理分析表明，CTF 对 Aβ42-Zn2+ 复合物的低聚物、β-折叠和原纤维形成有不同的影响。然而，在不存在或存在这些 CTF 的情况下，在分化的 PC-12 细胞中与 Aβ42-Zn2+ 复合物一起孵育的细胞活力实验表明，即使相对于 Aβ42 过量 10 倍，CTF 在存在 Zn2+ 的情况下也完全失去了抑制活性。鉴于这些结果，我们测试了另一种抑制剂分子镊子 CLR01，它恰好被证明对 Zn2+ 具有高亲和力，表明它可以破坏 Aβ42 寡聚化和 Aβ42-Zn2+ 络合。事实上，我们发现 CLR01 有效抑制 Aβ42-Zn2+ 复合物的毒性。此外，它的浓度低于单独抑制 Aβ42 毒性所需的浓度。与这些结果一致，CLR01 抑制 Aβ42-Zn2+ 复合物中的 β-折叠和原纤维形成。我们的数据表明，为了开发有效的治疗药物，应在相关金属离子存在的情况下检查 Aβ 自组装抑制剂和毒性，并且分子镊子可能是治疗开发特别有吸引力的候选者。
Oligomers of amyloid β-protein (Aβ) are thought to be the proximal toxic agents initiating the neuropathologic process in Alzheimer’s disease (AD). Therefore, targeting the self-assembly and oligomerization of Aβ has been an important strategy for designing AD therapeutics. In parallel, research into the metallobiology of AD has shown that Zn2+ can strongly modulate the aggregation of Aβ in vitro and both promote and inhibit the neurotoxicity of Aβ, depending on the experimental conditions. Thus, successful inhibitors of Aβ self-assembly may have to inhibit the toxicity not only of Aβ oligomers themselves but also of Aβ-Zn2+ complexes. However, there has been relatively little research investigating the effects of Aβ self-assembly and toxicity inhibitors in the presence of Zn2+. Our group has characterized previously a series of Aβ42 C-terminal fragments (CTFs), some of which have been shown to inhibit Aβ oligomerization and neurotoxicity. Here, we asked whether three CTFs shown to be potent inhibitors of Aβ42 toxicity maintained their activity in the presence of Zn2+. Biophysical analysis showed that the CTFs had different effects on oligomer, β-sheet, and fibril formation by Aβ42-Zn2+ complexes. However, cell viability experiments in differentiated PC-12 cells incubated with Aβ42-Zn2+ complexes in the absence or presence of these CTFs showed that the CTFs completely lost their inhibitory activity in the presence of Zn2+ even when applied at 10-fold excess relative to Aβ42. In light of these results, we tested another inhibitor, the molecular tweezer CLR01, which coincidentally had been shown to have a high affinity for Zn2+, suggesting that it could disrupt both Aβ42 oligomerization and Aβ42-Zn2+ complexation. Indeed, we found that CLR01 effectively inhibited the toxicity of Aβ42-Zn2+ complexes. Moreover, it did so at a lower concentration than needed for inhibiting the toxicity of Aβ42 alone. In agreement with these results, CLR01 inhibited β-sheet and fibril formation in Aβ42-Zn2+ complexes. Our data suggest that, for the development of efficient therapeutic agents, inhibitors of Aβ self-assembly and toxicity should be examined in the presence of relevant metal ions and that molecular tweezers may be particularly attractive candidates for therapy development.
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DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
2.9
作者：
GOOD, NE;WINGET, GD;SINGH, RMM
通讯作者：
SINGH, RMM
影响因子：
3.9
作者：
Ali, FE;Barnham, KJ;Separovic, F
通讯作者：
Separovic, F
影响因子：
7.3
作者：
Huang, Ling;Lu, Chuanjun;Li, Xingshu
通讯作者：
Li, Xingshu
影响因子：
2.9
作者：
Gessel, Megan Murray;Wu, Chun;Li, Huiyuan;Bitan, Gal;Shea, Joan-Emma;Bowers, Michael T.
通讯作者：
Bowers, Michael T.