3-Deoxyanthocyanidins inhibit β-amyloid aggregation, toxicity, and mitochondrial dysfunction: Evidence from MC-65...

Accumulation of amyloid-beta (Aβ₄₂) senile plaques in the brain is a hallmark of Alzheimer's disease (AD). Although some drug have been approvaled recently, none has demonstrated robust disease-modifying outcome. The 3-deoxyanthocyanidins (3-DXA) and their derivatives represent a more stable class of polyphenols, present at uniquely high concentrations in sorghum grains. Although 3-DXA exhibit strong potential to modulate protein aggregation processes, their effects on AD pathology remain unexplored. In this study, we investigated the inhibitory effects of three 3-DXA derivatives, apigeninidin chloride (AC), luteolinidin chloride (LC), and 7-methoxy apigeninidin (7-MAC), on Aβ₄₂ aggregation and associated neurotoxicity. Thioflavin T fluorescence assay was employed to assess alterations in Aβ₄₂ aggregation, while nuclear magnetic resonance spectroscopy and circular dichroism were used to evaluate compounds-protein interactions and secondary-structure changes. The neuroprotective effects of the three compounds were further examined in MC-65 cells under Aβ-induced toxicity. Additionally, generalized replica exchange with solute tempering based molecular dynamics simulations was conducted to explore the effects of AC and LC on Aβ₄₂ dimer stability and β-sheet disruption. Our findings demonstrate that AC, LC, and 7-MAC significantly reduced Aβ₄₂ aggregation by up to 88%, with AC and LC showing strong disruption of β-sheet structures. All three compounds significantly rescued MC-65 cells from Aβ₄₂-induced toxicity (62-77%), accompanied by enhanced mitochondrial activity. Molecular dynamics simulations analyses further revealed that AC and LC disrupted hydrophobic interactions within Aβ₄₂ dimers, contributing to destabilisation of neurotoxic aggregates. Overall, AC and LC exhibited strong multitarget activity against AD pathology by inhibiting Aβ₄₂ aggregation, restoring intracellular energy balance, and disrupting key neurotoxic structural motifs.