Chen Le, Hu Yilun, Cheng Yiyun, Wang Hui
South China Advanced Institute for Soft Matter Science and Technology, School of Emergent Soft Matter, South China University of Technology, Guangzhou 510640, China.
Guangdong Provincial Key Laboratory of Functional and Intelligent Hybrid Materials and Devices, South China University of Technology, Guangzhou 510640, China.
Nano Lett. 2024 Oct 1. doi: 10.1021/acs.nanolett.4c03275.
The accumulation of abnormal protein deposits known as amyloid-β (Aβ) plaques contributes to the development and progression of Alzheimer's disease. Aggregated Aβ exacerbates oxidative stress by stimulating the production of reactive oxygen species (ROS) in a detrimental feedback loop. 8-Hydroxyquinoline (8-HQ) is recognized for its ability to inhibit or reverse Aβ aggregation and reduce neurotoxicity. Here, an 8-HQ-based polymer, DHQ, was developed to combat Aβ-mediated neurotoxicity by delivering an antioxidant enzyme. DHQ efficiently delivers superoxide dismutase into targeted cells, thereby downregulating the intracellular ROS level. Additionally, the polymer effectively inhibits the fibrillization of three proteins involved in fibrosis, β-lactoglobulin (BLG), insulin, and Aβ1-40, at nanomolar concentrations. Cell culture models demonstrated that DHQ reduces ROS levels induced by Aβ1-40 aggregation, rescuing cell viability and preventing apoptosis. Intracellular delivery of SOD further enhanced the ability to maintain the ROS homeostasis. This polymer offers a multifaceted approach to treating diseases associated with amyloidosis.
被称为β淀粉样蛋白（Aβ）斑块的异常蛋白质沉积物的积累会导致阿尔茨海默病的发生和发展。聚集的Aβ通过在有害的反馈回路中刺激活性氧（ROS）的产生来加剧氧化应激。8-羟基喹啉（8-HQ）因其抑制或逆转Aβ聚集以及降低神经毒性的能力而闻名。在此，一种基于8-HQ的聚合物DHQ被开发出来，通过递送一种抗氧化酶来对抗Aβ介导的神经毒性。DHQ能有效地将超氧化物歧化酶递送至靶细胞，从而下调细胞内的ROS水平。此外，该聚合物在纳摩尔浓度下能有效抑制三种参与纤维化的蛋白质——β-乳球蛋白（BLG）、胰岛素和Aβ1-40的纤维化。细胞培养模型表明，DHQ降低了由Aβ1-40聚集诱导的ROS水平，挽救了细胞活力并防止细胞凋亡。超氧化物歧化酶的细胞内递送进一步增强了维持ROS稳态的能力。这种聚合物为治疗与淀粉样变性相关的疾病提供了一种多方面的方法。
