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<p>Alzheimer’s disease (AD) is characterized by neurodegeneration, autophagy dysregulation, and mitochondrial stress. β-asarone and tenuifolin have shown neuroprotective effects, but their mechanisms remain unclear. YuanZhi decoction, a traditional formula containing Polygala tenuifolia, is used for cognitive impairment, yet its active constituents are not fully understood. A D-galactose-induced AD mouse model (150&#xa0;mg/kg/day, s.c., 42 days) was established to evaluate β-asarone, tenuifolin, their combination, and YuanZhi decoction. Behavioral tests (MWM and NOR), Nissl staining, IHC, network pharmacology, molecular docking (including the GRIN2B inhibitor ifenprodil as positive control), Western blotting, biochemical assays, and RT-qPCR were performed. All treatments improved cognitive function, attenuated hippocampal neuronal loss and tau pathology, and restored metabolic parameters (ATP, ROS, DT, SOD2). Network pharmacology identified GRIN2B as a key hub target. Molecular docking revealed that β-asarone and senegenin (the active metabolite of tenuifolin) bind to the same allosteric pocket as ifenprodil on GRIN2B, sharing highly consistent interaction residues. GRIN2B upregulation in AD mice was accompanied by autophagic dysfunction (increased LC3B/LC3A ratio and PINK1, reduced p62) and mitochondrial stress. These abnormalities were significantly reversed by all treatments, with the combination and YuanZhi decoction showing greater efficacy. β-asarone, tenuifolin, their combination, and YuanZhi decoction alleviate GRIN2B-linked autophagic imbalance and mitochondrial stress in AD-like mice, supporting their therapeutic potential.</p> Graphical Abstract <p></p>

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β-Asarone, Tenuifolin, and YuanZhi Decoction Restore Cognitive Function and Modulate GRIN2B-Associated Autophagy in Alzheimer’s Disease

  • 期刊论文

  • 发表日期：

    2026年5月22日

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  • Haimin Tang,
  • Fang Peng,
  • Qian Shi,
  • Xiaomin Dai,
  • Feijun Hou,
  • Haiying Dong,
  • Li Zhang,
  • Zhifeng Shuai

摘要

Alzheimer’s disease (AD) is characterized by neurodegeneration, autophagy dysregulation, and mitochondrial stress. β-asarone and tenuifolin have shown neuroprotective effects, but their mechanisms remain unclear. YuanZhi decoction, a traditional formula containing Polygala tenuifolia, is used for cognitive impairment, yet its active constituents are not fully understood. A D-galactose-induced AD mouse model (150 mg/kg/day, s.c., 42 days) was established to evaluate β-asarone, tenuifolin, their combination, and YuanZhi decoction. Behavioral tests (MWM and NOR), Nissl staining, IHC, network pharmacology, molecular docking (including the GRIN2B inhibitor ifenprodil as positive control), Western blotting, biochemical assays, and RT-qPCR were performed. All treatments improved cognitive function, attenuated hippocampal neuronal loss and tau pathology, and restored metabolic parameters (ATP, ROS, DT, SOD2). Network pharmacology identified GRIN2B as a key hub target. Molecular docking revealed that β-asarone and senegenin (the active metabolite of tenuifolin) bind to the same allosteric pocket as ifenprodil on GRIN2B, sharing highly consistent interaction residues. GRIN2B upregulation in AD mice was accompanied by autophagic dysfunction (increased LC3B/LC3A ratio and PINK1, reduced p62) and mitochondrial stress. These abnormalities were significantly reversed by all treatments, with the combination and YuanZhi decoction showing greater efficacy. β-asarone, tenuifolin, their combination, and YuanZhi decoction alleviate GRIN2B-linked autophagic imbalance and mitochondrial stress in AD-like mice, supporting their therapeutic potential.

Graphical Abstract