State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Changchun, Jilin 130022, China.
University of Science and Technology of China, Hefei, Anhui 230026, China.
Anal Chem. 2021 Jan 26;93(3):1472-1479. doi: 10.1021/acs.analchem.0c03542. Epub 2020 Dec 21.
One of the pathogenesis hypotheses of Alzheimer's disease (AD) is amyloid depositions and neurofibrillary tangles. Apolipoprotein E (Apo E) acts a vital part in the development of AD by affecting the aggregation and clearance of amyloid-β (Aβ). In this paper, a dual polarization interferometry (DPI) technique was employed for a real-time investigation toward the binding events of Apo E isoforms, for instance, Apo E2, Apo E3, and Apo E4, with Aβ. By evaluation of detailed binding information provided by DPI, the affinities between Apo E isoforms and Aβ follow the order of E4 > E3 > E2, and the dissociation constants () of Aβ with Apo E2, Apo E3, and Apo E4 were determined to be 251 ± 37, 40 ± 0.65, and 24.6 ± 2.42 nM, respectively. Our findings reveal the isoform-specific binding behaviors from a kinetics perspective, which can help us understand that Apo E4 has a higher risk of causing AD because of its promoting effect on Aβ aggregation and fibrillation and inefficient clearance of Aβ. Remarkably, this work provides a promising method for exploring the dynamics of interactions between biomolecules and expectantly contributes to the development of AD drugs and therapies targeting Apo E and Aβ.
阿尔茨海默病（AD）的发病机制假说之一是淀粉样蛋白沉积和神经原纤维缠结。载脂蛋白 E（Apo E）通过影响淀粉样蛋白-β（Aβ）的聚集和清除，在 AD 的发展中起着至关重要的作用。在本文中，采用双偏振干涉（DPI）技术实时研究了载脂蛋白 E 异构体（如 Apo E2、Apo E3 和 Apo E4）与 Aβ 的结合事件。通过 DPI 提供的详细结合信息的评估，Apo E 异构体与 Aβ 的亲和力顺序为 E4 > E3 > E2，并且确定了 Aβ 与 Apo E2、Apo E3 和 Apo E4 的解离常数（）分别为 251 ± 37、40 ± 0.65 和 24.6 ± 2.42 nM。我们的研究结果从动力学角度揭示了异构体特异性的结合行为，这有助于我们理解 Apo E4 由于其促进 Aβ 聚集和纤维化以及 Aβ 清除效率低下而导致 AD 的风险更高。值得注意的是，这项工作为探索生物分子之间相互作用的动力学提供了一种有前途的方法，并有望为针对 Apo E 和 Aβ 的 AD 药物和治疗方法的发展做出贡献。
