Inhibition of amyloid β aggregation by venetoclax: a computational and in vitro experimental approach

Abstract

The aggregation of amyloid β-protein (Aβ) plays a key role in the pathological progression of Alzheimer's disease (AD). Given the current absence of effective therapeutic strategies, the drug repurposing approach provides novel insights into the treatment of AD. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, has demonstrated remarkable efficacy in the treatment of hematological malignancies, characterized by well-defined pharmacokinetic properties and a favorable safety profile. However, its effects and molecular mechanisms in the treatment of AD remain unexplored. Here, we investigated the potential of venetoclax in the inhibition of Aβ aggregation and elucidated its underlying mechanism. The inhibitory effect of venetoclax on Aβ aggregation was assessed using thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), and circular dichroism (CD) spectroscopy. Cellular assays were performed to evaluate the neuroprotective effects of venetoclax against Aβ42-induced neurotoxicity and oxidative stress. Molecular dynamics (MD) simulations were conducted to explore the molecular interactions between venetoclax and Aβ42 peptides. Venetoclax significantly inhibited Aβ aggregation, reduced fibril formation, and decreased β-sheet content at molar ratios of 2 : 1 and 1 : 1 (Aβ : venetoclax). Cellular assays showed that venetoclax attenuated Aβ42-induced neurotoxicity and oxidative stress. MD simulations revealed that venetoclax stabilized Aβ peptides via hydrogen-bonding networks, increasing solvent accessibility and reducing hydrophobic interactions. Venetoclax inhibited Aβ aggregation and mitigated Aβ-induced neurotoxicity by stabilizing Aβ peptide dynamics. These findings support the potential of venetoclax as a repurposed therapeutic candidate for AD.