Xanthohumol destabilizes the structure of amyloid-β (Aβ) oligomers and promotes the formation of high-molecular-weight amorphous aggregates

This study provides a comprehensive structural analysis of prenylflavonoids (PFs) interaction with Aβ1–42 oligomers, revealing their potential to modulate amyloid peptide aggregation pathways. Among the tested PFs, xanthohumol (XN), isoxanthohumol (IXN) and 8-prenylnaringenin (8-PN), XN exhibited the strongest anti-amyloidogenic activity, inhibiting Aβ1–42 aggregation at substoichiometric concentrations and stabilizing the peptide in amorphous aggregates. Its higher conformational flexibility drives the distinct interaction profile and protective effect; in fact, XN forms stable complexes with Aβ1–42 oligomers, preventing their transition to β-sheet-rich fibrils. These findings highlight that XN may offer a neuroprotective strategy by redirecting Aβ1–42 aggregation toward less toxic species, in agreement with its previously described ability to reduce Aβ toxicity. Our data dissect the anti-amyloidogenic mechanism of action of XN at molecular level, providing structural insights for the rational design of a new class of Aβ inhibitors. Indeed, conventional drug discovery approaches are often ineffective against amyloid aggregates, due to their dynamic and atypical receptor structures. Instead, preventive and therapeutic strategies should focus on compounds that form stable supramolecular complexes, capable of modulating the structure and toxicity of the aggregates without relying on specific binding sites. Additionally, due also to its anti-oxidant activity, XN, naturally present in hops, shows promise as nutraceutical for Alzheimer's disease prevention. Dietary supplementation with XN could modulate early molecular events linked to neurodegeneration, providing a safe, sustainable approach to neuroprotection.