Di-caffeoylquinic acid: a potential inhibitor for amyloid-beta aggregation

• DOI: 10.1007/s11418-024-01825-y
• Publication Date: 2024-06-27T03:40:43Z
• Authors: Yue Sun; Xue Wang; Xiaoyu Zhang; Yan Li; Dongdong Wang; Feng Sun; Cunli Wang; Zhenqiang Shi; Xindi Yang; Zhiying Yang; Haijie Wei; Yanling Song; Guangyan Qing
• Keywords: Molecular Docking Simulation; Protein Aggregates; Amyloid beta-Peptides; Alzheimer Disease; Quinic Acid; Humans; Peptide Fragments

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) 15N-1H 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.