手性纳米粒子选择性识别β-淀粉样肽及调控其聚集行为的研究

β-amyloid peptide (Aβ), as the major constituent of senile plaques, plays a crucial role in the development and progress of Alzheimer's disease (AD). The toxicity of Aβ is dependent on its aggregational state. Evidences have shown that a variety of biological macromolecules can interact with Aβ and change its aggregation properties and toxicity. Studies on molecular structures of Aβ aggregates and the interaction mechanism between Aβ and other related biomolecules, especially chiral recognition, are of great importance for a deep insight into the in vivo behaviors of Aβ and the role of Aβ in AD pathogenesis at the molecular level. In this project, chiral gold nanoparticles will be utilized to mimic biological macromolecules. The influence of particle size and surface capping ligands on chiral recognition between chiral gold nanoparicles and Aβ as well as their ability to modulate Aβ aggregation will be discussed. Furthermore, the chiral nanoparticles-binding sites on Aβ and binding models between them will be established. This will be helpful to evaluate the potential applications of chiral nanomaterials as anti-AD chiral drugs. In addition, based on the optical properties of gold nanoparticles, the influences of different aggregated forms of Aβ on chiral nanoparticles will be monitored. Through the use of this method, we can screen the chiral nanoparticles which can target to a single specific Aβ assembly form especially the more toxic Aβ oligomers. The results of this project will help to design nano-probes for detection of Aβ aggregation and provide new strategies for early diagnosis of AD.

作为老年斑的主要成分，β-淀粉样肽（β-amyloid peptide, Aβ）在阿尔茨海默症（AD）的发生和发展中起着至关重要的作用。Aβ的毒性与其聚集状态密切相关。研究表明许多生物大分子能够与Aβ作用并调控其聚集过程及神经毒性。探讨Aβ不同聚集体的分子结构及其与体内相关生物大分子的相互作用尤其是手性识别，对进一步理解Aβ在体内的作用模式、在分子水平上揭示Aβ的致病机制有重要意义。本项目以手性金纳米颗粒模拟生物大分子，考察其尺寸和表面手性配体对其与Aβ手性识别作用和调控Aβ聚集活性的影响，测定手性金纳米颗粒与Aβ的结合位点，建立结合模型，评估其作为抗AD手性药物的应用前景。此外，基于金纳米颗粒的光学特性，探究不同聚集形态的Aβ对其光学性质的影响，筛选出对毒性较大的Aβ寡聚体特异性响应的手性纳米颗粒，设计Aβ聚集检测探针，为AD的早期诊断提供新的思路。

β-淀粉样肽（Aβ）的聚集和沉积与阿尔茨海默症（AD）的发生和发展密切相关。设计以Aβ为靶点的新型诊疗试剂是预防和治疗AD的重要策略。本项目以氨基酸、酒石酸等为手性配体理性设计并合成了一系列手性纳米粒子，以此模拟体内生物大分子，考察了其尺寸、表面手性配体以及结构对其与Aβ的手性识别作用和调控Aβ聚集活性的影响，测定了手性纳米粒子与Aβ的结合位点，并建立了结合模型，评估了其作为Aβ聚集抑制剂在体内的抗AD效果。此外，探讨了Aβ在体内拥挤环境下的行为，并在此基础上，设计了多种新型多功能纳米材料，用于AD的早期诊断、治疗与药物筛选等领域。该项目对在分子水平上揭示Aβ的致病机制具有重要意义，为设计以Aβ为靶点的有效药物提供了新的研究思路。本项目所取得的系列成果将为与蛋白质错误折叠相关疾病的诊疗试剂的开发提供理论与技术支持。