Aug 2026· RSC Advances· Vol 16, pp. 44479 - 44489· 0 citations· 41 references
Medicine
TL;DR
Findings support the potential of venetoclax as a repurposed therapeutic candidate for AD in the inhibition of Aβ aggregation and mitigated Aβ-induced neurotoxicity by stabilizing Aβ peptide dynamics.
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.
In this study, molecular-level insights are provided into the interaction mechanisms of γ-secretase inhibitors, contributing to a better understanding of structure-energy relationships that are essential for the rational design of more selective and effective therapeutic agents for Alzheimers disease.
W. S. Clemente, K. S. Bezerra, E. Matias et al.· Physical Chemistry, Chemical...· 0 citations
There is growing evidence supporting the potential role of microbial infections in the aetiology of Alzheimer’s disease (AD). We aim to evaluate the effect of raltegravir, either alone as a single therapy or combined with elacridar, a P-gp/BCRP inhibitor, on AD-related pathways in vitro.
Flow cytometry combined was used to quantify the expression of key inflammatory markers, including interleukin-1β (IL-1β), NLRP3 inflammasome components, costimulatory molecules (CD86), and the class B scavenger receptor (SR-B2) CD163, in HMC3 human microglia cells. Furthermore, the effect of raltegravir on Aβ1-42-induced p-tau 181 expression in H4 human neuroglioma cells was assessed.
Results. Our data indicate that raltegravir significantly (p < 0.01) abolishes the Aβ1-42-stimulating effect on p-tau 181, and that this effect involves the downregulation of PP2Aα+β. The observed reduction of p-tau 181 by raltegravir is potentially mediated by the inhibition of tau-phosphatases. Aβ1-42 significantly upregulated the expression of the surface receptors CD86 and CD163 in HMC3 microglial cells. Raltegravir treatment significantly reduced CD86 expression, while it had no significant effect on Aβ1-42-induced CD163 expression (p > 0.05). Further,raltegravir significantly (p < 0.05) attenuated IL-1β cytokine release, likely via downregulation of NLRP3-inflammasome signalling pathway in microglia.
Taken together, our findings suggest that raltegravir exerts a neuroprotective effect by targeting pathological events associated with AD, particularly tau phosphorylation and neuroinflammation.
n/a
Neuroimmunology (NEUR)
Tamas Fulop, Hicham Berrougui, Ton Bunt et al.· Journal of Immunology· 0 citations
Amyloid-β (Aβ) is a neurotoxic substance, and studies have found that its excessive deposition in the brain, forming senile plaques, is a major pathological feature of Alzheimer's disease (AD). In previous studies, Ribisin A, a benzofuran compound, was purified from Phellinus ribis and found to have neuroprotective effects. This study aims to elucidate the neuroprotective mechanism of Ribisin A in an Aβ25-35-damaged PC12 cell model. This study established an in vitro AD model using PC12 cells damaged by Aβ25-35. We applied methyl tetrazolium (MTT), enzyme-linked immunosorbent assay (ELISA) kits, flow cytometry, and western blotting techniques to study the effects of Ribisin A on the Aβ25-35 injury model and the relationship with the ERK pathway from the aspects of cell injury degree, cytokine content, Calcium ion (Ca2 +) concentration, mitochondrial membrane potential (MMP), and the ERK pathway-related protein expression. Results indicate that Ribisin A reduced lactate dehydrogenase (LDH), reactive oxygen species (ROS), tumour necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels in the Aβ25-35-induced cellular injury model while increasing superoxide dismutase (SOD) levels. Furthermore, it inhibited Aβ25-35-induced increases in Ca²⁺ concentration and decreases in MMP, leading to upregulation of ERK pathway-related proteins TrkB, p-ERK1/2, and p-CREB, with significant elevations in p-ERK/ERK and p-CREB/CREB ratios (P < 0.01). Ribisin A can reduce oxidative damage, inhibit inflammation, restore mitochondrial function, and reduce apoptosis. The neuroprotective mechanism of Ribisin A may involve regulation of the TrkB-mediated ERK/CREB signaling cascade. Our study provides evidence for the neuroprotective mechanism of Ribisin A in an Aβ25-35-induced cellular injury model.
Xinyue Du, Mengyu Bao, Yuanyuan Li et al.· Tissue & Cell· 0 citations
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that involves the formation of amyloid-β (Aβ) aggregates, and the development of targeted therapeutic strategies is needed. In the current work, we report the rational design of H102-CP05, a 22-residue chimeric peptide that integrates the β-sheet breaker peptide H102 with the CD63-targeting anchor CP05 to enable extracellular vesicle (EV)-mediated delivery of an Aβ-inhibitory payload. Computational analysis confirmed favorable physicochemical properties and a non-allergenic profile. In silico immunogenicity assessment and C-IMMSIM simulation demonstrated a low risk of anti-drug antibody formation under chronic dosing conditions. Homology modelling and HADDOCK docking (score: -147.2 ± 4.6) predicted a computationally favourable CD63 binding configuration, while 100 ns molecular dynamics simulations confirmed structural stability in both aqueous and EV-mimetic lipid bilayer environments. In vitro cytotoxicity against HEK-293 cells revealed no significant toxicity (10-100 µM). Zebrafish embryo studies indicated acceptable developmental safety at lower concentrations, with concentration-dependent bradycardia observed at higher doses warranting further cardiovascular evaluation. Thioflavin T fluorescence assays demonstrated dose-dependent inhibition of Aβ fibrillation, with near-complete suppression at 100 µM. These findings collectively support H102-CP05 as a promising EV-displayed therapeutic candidate for AD.
V. Singh, Raja Natesan Sella· Journal of drug targeting (P...· 0 citations
Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by amyloid- β aggregation, oxidative stress, neuroinflammation, tau hyperphosphorylation, and cholinergic dysfunction. The limited efficacy of current therapies has driven the development of multitargetdirected ligands (MTDLs). Chalcones represent a versatile scaffold for modulating multiple ADrelated targets. This review provides a concise analysis of the structure-activity relationship (SAR) of chalcone derivatives, highlighting the effects of hydroxylation, methoxylation, halogenation, and heterocyclic hybridization on biological activity. Electron-withdrawing substituents (e.g., halogens, -CF₃) enhance enzyme inhibition and MAO-B selectivity, whereas electron-donating groups (e.g., hydroxyl and methoxy groups) contribute to antioxidant activity, metal chelation, and hydrogen bonding interactions. Scaffold hybridization and optimized linker design further improve multitarget engagement, including AChE/BuChE inhibition, MAO-B modulation, and anti-amyloid activity. However, despite promising in vitro and in silico findings, translational limitations remain due to insufficient in vivo validation and pharmacokinetic constraints. Overall, chalcone-based MTDLs provide a rational framework for the development of next-generation anti-Alzheimer agents.
Deepika Paliwal, Aman Thakur· Mini-Reviews in Medical Chem...· 0 citations
The findings indicate that RNA aptamers, such as 1R6, may represent promising therapeutic candidates for synucleinopathies, thus opening new avenues in the treatment of these diseases.
K. Murakami, Thi Hong Van Nguyen, L. Tsuda et al.· bioRxiv· 1 citation
