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3-Deoxyanthocyanidins inhibit β-amyloid aggregation, toxicity, and mitochondrial dysfunction: Evidence from MC-65 cells and molecular dynamics simulations
Journal article   Open access   Peer reviewed

3-Deoxyanthocyanidins inhibit β-amyloid aggregation, toxicity, and mitochondrial dysfunction: Evidence from MC-65 cells and molecular dynamics simulations

Rasheed A. Abdulraheem, Ammar U. Danazumi, Philipp Nitschke, Luke Gray Whiley, Abdulrahman Ibrahim Tudu, Ranil Coorey, Zhoyu Li, Prashant Bharadwaj, Vijay Jayasena, Stuart K. Johnson, …
Free radical biology & medicine, Vol.247, pp.213-223
2026
DOI: https://doi.org/10.1016/j.freeradbiomed.2026.01.061
PMID: 41633420
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Published4.09 MBDownloadView
CC BY-NC V4.0,  Open Access

Abstract

3-Deoxyanthocyanidins Alzheimer's disease Amyloid aggregation Neurotoxicity
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. [Display omitted] •Sorghum bicolor grains have uniquely high content of 3-deoxyanthocyanidins (3-DXA).•The three compounds inhibit Aβ42 aggregation by 88%, disrupting β-sheet structures.•The compounds significantly rescue MC-65 cells from Aβ42-induced neurotoxicity.•The compounds inhibit mitochondrial dysfunction in a dose-dependent manner.•The 3-DXA derivatives disrupt hydrophobic interactions in Aβ42 dimers.

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