6-gingerol interferes with amyloid-beta (Aβ) peptide aggregation

Alzheimer's disease (AD) is the most prevalent age-related cause of dementia. AD affects millions of people worldwide, and to date there is no cure. The pathological hallmark of AD brains is deposition of amyloid plaques, which mainly consist of amyloid-β (Aβ) peptides, commonly 40 or 42 residues long, that have aggregated into amyloid fibrils. Intermediate aggregates in the form of soluble Aβ oligomers appear to be highly neurotoxic. Cell and animal studies on mice have previously demonstrated positive effects of the molecule 6-gingerol on AD pathology. Gingerols are the main active constituents of the ginger root, which in many cultures is a traditional nutritional supplement for memory enhancement. Here, we use biophysical experiments to characterize in vitro interactions between 6-gingerol and Aβ₄₀/Aβ₄₂ peptides. Our experiments with atomic force microscopy (AFM) imaging show that the hydrophobic 6-gingerol molecule interferes with Aβ aggregation, by interfering with fibril elongation and by promoting formation of amorphous agglomerates. Interestingly, also the DMSO solvent was found to induce formation of amorphous Aβ agglomerates, which appears to be a novel observation. Our experiments with nuclear magnetic resonance (NMR) and Thioflavin-T (ThT) fluorescence spectroscopy show that 6-gingerol has no or very little interaction with Aβ monomers. Taken together, these results might provide a molecular explanation, at least in part, for the previously observed beneficial effects of 6-gingerol on AD pathology. Given its favourable toxicity profile, 6-gingerol appears to have many of the desired properties of an anti-AD compound.