Mangiferin as a Novel In Vitro Polyphenolic Inhibitor of Amyloid Aggregation

Amyloid aggregation is a pathological hallmark of several neurodegenerative disorders, including Alzheimer's disease. Polyphenolic compounds are emerging as promising candidates for therapeutic intervention due to their capacity to interfere with multiple stages of amyloidogenesis. In this study, we investigated, in vitro, the antiamyloidogenic potential of mangiferin (MGF), a xanthonoid polyphenol with established pharmacological activity but previously unexplored in the context of amyloid modulation. Using a combination of biophysical, spectroscopic, and microscopic techniques, we assessed the effects of MGF on the aggregation behavior of two distinct amyloidogenic peptides: Aβ_1-42 and Cterm_mutA. Thioflavin T (ThT) assays revealed that MGF significantly inhibited aggregation in a concentration-dependent manner, with maximal inhibition at a 1:5 peptide:MGF ratio. Nanoparticle tracking analysis (NTA) and microscopy studies demonstrated peptide-specific differences in the mechanism of action of MGF: MGF promoted the formation of larger, nonfibrillar oligomers in Aβ_1-42, while it reduced oligomer size in Cterm_mutA. This effect was most likely attributable to the disruption of π-π interactions. Importantly, MGF exhibited no cytotoxicity in SH-SY5Y cells and significantly attenuated the amyloid-induced toxicity of both peptides. These findings highlight MGF as a promising, multitargeted modulator of amyloid aggregation with potential applications in neuroprotection and the development of novel antiamyloid therapies.