Kaur Harminder, Saikia Biman, Choudhary Gajendra, Prajapat Manisha, Ghosh Ketaki, Ghosh Subrata, Mondal Prasenjit, Prakash Ajay, Medhi Bikash
Department of Immunopathology, PGIMER, Chandigarh, India.
Department of Pharmacology, PGIMER, Chandigarh, India.
Metab Brain Dis. 2025 Sep 16;40(7):268. doi: 10.1007/s11011-025-01665-z.
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.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征为突触功能障碍和神经元丢失，谷氨酸兴奋性毒性在其病理过程中起核心作用。负责维持突触谷氨酸稳态的星形胶质细胞谷氨酸转运体EAAT2在AD中显著下调。恢复EAAT2表达是一种有前景的治疗策略。本研究探索通过靶向Axin-1/β-连环蛋白相互作用来调节Wnt/β-连环蛋白信号通路以提高EAAT2水平的潜力。通过对Asinex-CNS数据库中的120993种化合物进行虚拟筛选，基于分子对接、MMGBSA评分和类药性质参数鉴定出了5种先导候选物。包括主成分分析、动态交叉相关映射、分子动力学模拟和MM/PBSA结合自由能计算在内的先进计算机模拟分析突出显示BAS 04937103是破坏β-连环蛋白降解最有前景的化合物。使用C6胶质瘤细胞和原代星形胶质细胞培养物进行的体外验证表明，BAS 04937103增强了β-连环蛋白的稳定性和核转位，降低了Axin-1表达，并显著上调了EAAT2水平。这些分子效应与细胞外谷氨酸浓度降低、谷氨酸摄取改善和氧化应激减轻相对应。总体而言，这些发现确立了BAS 04937103作为Axin/β-连环蛋白相互作用的新型调节剂，在减轻阿尔茨海默病中谷氨酸介导的神经毒性方面具有治疗潜力。
