State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Mar Drugs. 2020 Sep 25;18(10):488. doi: 10.3390/md18100488.
It is proven that β-amyloid (Aβ) aggregates containing cross-β-sheet structures led to oxidative stress, neuroinflammation, and neuronal loss via multiple pathways. Therefore, reduction of Aβ neurotoxicity via inhibiting aggregation of Aβ or dissociating toxic Aβ aggregates into nontoxic forms might be effective therapeutic methods for Alzheimer's disease (AD) treatment. This study was designed to explore interference of chitosan oligosaccharides (COS) on β-(1-42)-amyloid protein (Aβ42) aggregation and Aβ42-induced cytotoxicity. Here it was demonstrated that COS showed good blood-brain barrier (BBB) penetration ability in vitro and in vivo. The experimental results showed that COS efficiently interfered with Aβ42 aggregation in dose- and degree of polymerization (DP)-dependent manners, and COS monomer with DP6 showed the best effect on preventing conformational transition into β-sheet-rich structures. Based on the binding affinity analysis by microscale thermophoresis (MST), it was confirmed that COS could directly bind with Aβ42 in a DP-dependent manner. Our findings demonstrated that different performance of COS monomers with different DPs against Aβ42 assembly was, to some extent, attributable to their different binding capacities with Aβ42. As a result, COS significantly ameliorated Aβ42-induced cytotoxicity. Taken together, our studies would point towards a potential role of COS in treatment of AD.
已有研究证明，β-淀粉样蛋白（Aβ）聚集物中含有交叉β-折叠结构，通过多种途径导致氧化应激、神经炎症和神经元丢失。因此，通过抑制 Aβ 聚集或使有毒的 Aβ 聚集物解离成无毒形式来减少 Aβ 神经毒性，可能是治疗阿尔茨海默病（AD）的有效方法。本研究旨在探索壳寡糖（COS）对β-（1-42）-淀粉样蛋白（Aβ42）聚集和 Aβ42 诱导的细胞毒性的干扰作用。结果表明，COS 具有良好的血脑屏障（BBB）穿透能力，无论是在体外还是体内实验中。实验结果表明，COS 以剂量和聚合度（DP）依赖的方式有效地干扰 Aβ42 的聚集，DP6 的 COS 单体对阻止构象向富含β-折叠的结构转变具有最佳效果。通过微量热泳动（MST）的结合亲和力分析，证实 COS 可以与 Aβ42 以 DP 依赖的方式直接结合。我们的研究结果表明，不同 DP 的 COS 单体对 Aβ42 组装的不同性能，在一定程度上归因于它们与 Aβ42 的不同结合能力。结果，COS 显著改善了 Aβ42 诱导的细胞毒性。总之，我们的研究表明 COS 在 AD 的治疗中可能具有潜在作用。
