Probing the anti-Aβ42 aggregation and protective effects of prenylated xanthone against Aβ42-induced toxicity in transgenic Caenorhabditis elegans model

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) protein aggregates, leading to synaptic dysfunction and neuronal cell death. In this study, we used a comprehensive approach encompassing in vitro assays, computational analyses, and an in vivo Caenorhabditis elegans model to evaluate the inhibitory effects of various xanthones, focusing on Garcinone D (GD), on Aβ42 oligomer formation. Dot blot analysis revealed concentration-dependent responses among xanthones, with GD consistently inhibiting Aβ42 oligomer formation at low concentrations (0.1 and 0.5 μM, inhibitions of 84.66 ± 2.25% and 85.06 ± 6.57%, respectively). Molecular docking and dynamics simulations provided insights into the molecular interactions between xanthones and Aβ42, highlighting the disruption of key residues involved in Aβ42 aggregation. The neuroprotective potential of GD was established using transgenic C. elegans GMC101, with substantial delays in paralysis reported at higher concentrations. Our findings show that GD is a potent suppressor of Aβ42 oligomer formation, suggesting its potential as a therapeutic candidate for AD. The concentration-dependent effects observed in both in vitro and in vivo models underscore the need for nuanced dose-response assessments. These findings contribute novel insights into the therapeutic landscape of xanthones against AD, emphasizing the multifaceted potential of GD for further translational endeavors in neurodegenerative disorder research. [Display omitted] •In vitro, in silico, and in vivo study was performed to investigate the inhibitory effects of prenylated xanthones on Aβ42 aggregation.•Garcinone D showed significant inhibitory effects towards Aβ42 aggregation at nano-molar concentrations.•Garcinone D interacts with Gln15, a key residue that disrupts Aβ42 oligomer formation via molecular docking and dynamics.•Garcinone D significantly delays worm paralysis in a transgenic C. elegans model.