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

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Alzheimer's disease (AD) is a neurodegenerative disorder with limited treatment options.
• Traditional Chinese Medicine (TCM) offers a potential source for novel AD therapeutics.
• Amyloid-beta (Aβ) (1-40) aggregation is a key pathological hallmark of AD.

Purpose of the Study:

• To screen TCM compounds for their ability to inhibit Aβ (1-40) aggregation.
• To identify specific molecular interactions and mechanisms of action.
• To evaluate the therapeutic potential and cellular effects of identified compounds.

Main Methods:

• Thioflavin T fluorescence assay for screening Aβ (1-40) aggregation inhibitors.
• Nuclear Magnetic Resonance (NMR) spectroscopy (2D ¹⁵N-¹H heteronuclear single quantum coherence) for molecular interaction analysis.
• Molecular docking simulations to predict binding modes.
• Cellular assays to assess toxicity, mitochondrial membrane potential, apoptosis, and Aβ (1-40)-induced damage.

Main Results:

• Eight TCM compounds inhibited Aβ (1-40) aggregation; 1,3-di-caffeoylquinic acid showed the strongest binding affinity (KD = 26.7 nM).
• 1,3-di-caffeoylquinic acid disrupts Aβ (1-40) aggregation via interactions with phenolic hydroxyl and amino acid residues, notably Met-35.
• Identified compounds, especially 1,3-di-caffeoylquinic acid, exhibited low toxicity and protected cells by regulating mitochondrial function and reducing apoptosis.

Conclusions:

• 1,3-di-caffeoylquinic acid is a potent inhibitor of Aβ (1-40) aggregation with therapeutic potential for AD.
• This study elucidates the molecular mechanisms by which TCM compounds interfere with Aβ (1-40) aggregation.
• Catechol compounds from TCM represent a promising avenue for developing novel Alzheimer's disease interventions.