College of Chemical Engineering, Shenyang University of Chemical Technology, Shenyang, 110142, China.
State Key Laboratory of Medical Proteomics, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, National Chromatographic R. & A. Center, Chinese Academy of Sciences, Dalian, 116023, China.
J Nat Med. 2024 Sep;78(4):1029-1043. doi: 10.1007/s11418-024-01825-y. Epub 2024 Jun 27.
Alzheimer's disease (AD) remains a challenging neurodegenerative disorder with limited therapeutic success. Traditional Chinese Medicine (TCM), as a promising new source for AD, still requires further exploration to understand its complex components and mechanisms. Here, focused on addressing Aβ (1-40) aggregation, a hallmark of AD pathology, we employed a Thioflavin T fluorescence labeling method for screening the active molecular library of TCM which we established. Among the eight identified, 1,3-di-caffeoylquinic acid emerged as the most promising, exhibiting a robust binding affinity with a KD value of 26.7 nM. This study delves into the molecular intricacies by utilizing advanced techniques, including two-dimensional (2D) N-H heteronuclear single quantum coherence nuclear magnetic resonance (NMR) and molecular docking simulations. These analyses revealed that 1,3-di-caffeoylquinic acid disrupts Aβ (1-40) self-aggregation by interacting with specific phenolic hydroxyl and amino acid residues, particularly at Met-35 in Aβ (1-40). Furthermore, at the cellular level, the identified compounds, especially 1,3-di-caffeoylquinic acid, demonstrated low toxicity and exhibited therapeutic potential by regulating mitochondrial membrane potential, reducing cell apoptosis, and mitigating Aβ (1-40)-induced cellular damage. This study presents a targeted exploration of catechol compounds with implications for effective interventions in AD and sheds light on the intricate molecular mechanisms underlying Aβ (1-40) aggregation disruption.
阿尔茨海默病（AD）仍然是一种具有挑战性的神经退行性疾病，治疗效果有限。传统中药（TCM）作为 AD 的一个有前途的新来源，仍需要进一步探索，以了解其复杂的成分和机制。在这里，我们专注于解决 Aβ（1-40）聚集，AD 病理学的一个标志，我们采用了 Thioflavin T 荧光标记法对我们建立的 TCM 活性分子文库进行筛选。在鉴定的八种化合物中，1,3-二咖啡酰奎宁酸表现出最强的潜力，与 KD 值为 26.7 nM 的 Aβ（1-40）具有强大的结合亲和力。这项研究利用二维（2D）N-H 异核单量子相干核磁共振（NMR）和分子对接模拟等先进技术深入研究了分子复杂性。这些分析表明，1,3-二咖啡酰奎宁酸通过与特定的酚羟基和氨基酸残基相互作用，特别是在 Aβ（1-40）中的 Met-35 上，破坏 Aβ（1-40）的自聚集。此外，在细胞水平上，鉴定出的化合物，特别是 1,3-二咖啡酰奎宁酸，通过调节线粒体膜电位、减少细胞凋亡和减轻 Aβ（1-40）诱导的细胞损伤，表现出低毒性和治疗潜力。这项研究对儿茶素类化合物进行了有针对性的探索，为 AD 的有效干预提供了启示，并阐明了 Aβ（1-40）聚集破坏的复杂分子机制。
