A novel modulator of the Axin/β-Catenin interaction to restore EAAT2 expression in alzheimer’s disease: an in-silico and in-vitro approach

Sep 16, 2025Metabolic brain disease

A new regulator of the Axin/β-Catenin interaction to restore brain glutamate transporter levels in Alzheimer's disease using computer and lab studies

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Abstract

Five lead candidates were identified from a screening of 120,993 compounds targeting the Axin-1/β-catenin interaction.

Alzheimer's disease is associated with reduced levels of the glutamate transporter EAAT2, leading to synaptic dysfunction.
Modulating the Wnt/β-catenin signaling pathway may enhance EAAT2 expression.
BAS 04937103 was identified as the most promising compound for stabilizing β-catenin and increasing EAAT2 levels.
In vitro studies showed that BAS 04937103 decreased Axin-1 expression and increased glutamate uptake.
These molecular changes corresponded with lower extracellular glutamate concentrations and reduced oxidative stress.

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by synaptic dysfunction and neuronal loss, with glutamate excitotoxicity playing a central role in its pathology. The astrocytic glutamate transporter EAAT2, responsible for maintaining synaptic glutamate homeostasis, is significantly downregulated in AD. Restoration of EAAT2 expression presents a promising therapeutic strategy. This study explores the potential of modulating the Wnt/β-catenin signaling pathway to enhance EAAT2 levels by targeting the Axin-1/β-catenin interaction. Through virtual screening of 120,993 compounds from the Asinex-CNS database, five lead candidates were identified based on molecular docking, MMGBSA scores, and drug-likeness parameters. Advanced in-silico analyses-including Principal Component Analysis, Dynamic Cross-Correlation Mapping, molecular dynamics simulations, and MM/PBSA binding free energy calculations-highlighted BAS 04937103 as the most promising compound for disrupting β-catenin degradation. In vitro validation using C6 glioma cells and primary astrocytic cultures demonstrated that BAS 04937103 enhanced β-catenin stabilization and nuclear translocation, reduced Axin-1 expression, and significantly upregulated EAAT2 levels. These molecular effects corresponded with decreased extracellular glutamate concentrations, improved glutamate uptake, and reduced oxidative stress. Collectively, these findings establish BAS 04937103 as a novel modulator of the Axin/β-catenin interaction with therapeutic potential in mitigating glutamate-mediated neurotoxicity in Alzheimer's disease.

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A novel modulator of the Axin/β-Catenin interaction to restore EAAT2 expression in alzheimer’s disease: an in-silico and in-vitro approach

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