Cobalt(III) Schiff base complexes stabilize non-fibrillar amyloid-β aggregates with reduced toxicity.
Cobalt(III) Schiff base complexes stabilize non-fibrillar amyloid-β aggregates with reduced toxicity.
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钴(III) 席夫碱复合物可稳定非纤维状淀粉样β 聚集体，并降低毒性。
DOI：
10.1016/j.jinorgbio.2020.111265
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发表时间：
2020
影响因子：
3.9
通讯作者：
Meade,ThomasJ
中科院分区：
文献类型：
--
作者：
Roberts,KaleighF;Brue,ChristopherR;Preston,Anna;Baxter,Damonick;Herzog,Emma;Varelas,Eleni;Meade,ThomasJ
淀粉样蛋白(Aβ，Aβ)的聚集被认为是阿尔茨海默病(AD)发病机制的基础，体外聚集动力学已被证明与AD患者和动物模型的疾病进展速度相关，因此被证明是测试Aβ靶向治疗的有用指标。在这里，我们提出了钴(III)席夫碱配合物([Co(乙酰丙酮)(NH_3)_2]Cl；Co(III)-Sb)通过各种补充技术调节Aβ聚集动力学的证据。其中包括硫代黄素T(THT)荧光、圆二色谱(CD)、透射电子显微镜(TEM)和原子力显微镜(AFM)。利用Knowles等人建立的数学模型，我们的数据符合动力学速率定律。为了提取Co(III)-Sb对聚集动力学影响的机理信息。我们的分析表明，Co(III)-Sb通过降低聚合速度和提高成核速度改变了Aβ的聚集，这表明Co(III)-Sb使Aβ迅速稳定低聚物种，并减少了向成熟纤维的伸长。这一结果得到了Aβ体外聚集体的电子显微镜和原子力显微镜的证实。我们还证明，与未经处理的样品相比，在Co(III)-Sb存在下产生的Aβ聚集体混合物显示出较低的细胞毒性。
The aggregation of amyloid-β (Aβ) is believed to be foundational to the pathogenesis of Alzheimer's disease (AD).In vitroaggregation kinetics have been shown to correlate with rates of disease progression in both AD patients and animal models, thus proving to be a useful metric for testing Aβ-targeted therapeutics. Here we present evidence of cobalt(III) Schiff base complex ([Co(acetylacetonate)(NH3)2]Cl; Co(III)-sb) modulation of Aβ aggregation kinetics by a variety of complementary techniques. These include Thioflavin T (ThT) fluorescence, circular dichroism (CD) spectroscopy, transmission electron microscopy (TEM), and atomic force microscopy (AFM). Our data was fitted to kinetic rate laws using a mathematical model developed by Knowles et al. in order to extract mechanistic information about the effect of Co(III)-sb on aggregation kinetics. Our analysis revealed that Co(III)-sb alters Aβ aggregation by decreasing the polymerization rate and increasing the nucleation rate, suggesting that Co(III)-sb causes Aβ to rapidly stabilize oligomeric species with reduced elongation into mature fibrils. This result was corroborated by TEM and AFM of Aβ aggregatesin vitro. We also demonstrate that Aβ aggregate mixtures produced in the presence of Co(III)-sb exhibit decreased cytotoxicity compared to untreated samples.