2. Academic Validation
  3. Ajugol ameliorates mitochondrial dysfunction and cognitive decline in Alzheimer's Disease via BNIP3-dependent mitophagy

Ajugol ameliorates mitochondrial dysfunction and cognitive decline in Alzheimer's Disease via BNIP3-dependent mitophagy

  • Neuropharmacology. 2026 Jun 15:291:110923. doi: 10.1016/j.neuropharm.2026.110923.
Yuan Qiao 1,  Mengmeng Huang 2,  Cuiting Sun 2,  Xiaochen Du 3,  Yuye Wang 4,  Yuchen Liu 3,  Linwei Zhang 4,  Yingjie Guo 5,  Liang Peng 6,  Dantao Peng 7
Affiliations

Affiliations

  • 1 China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Department of Neurology, China-Japan Friendship Hospital, Beijing, China; Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, China.
  • 2 Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, China; China-Japan Friendship Hospital, Capital Medical University, Beijing, China.
  • 3 China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Department of Neurology, China-Japan Friendship Hospital, Beijing, China.
  • 4 Department of Neurology, China-Japan Friendship Hospital, Beijing, China.
  • 5 Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, China.
  • 6 China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, China. Electronic address: [email protected].
  • 7 China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Department of Neurology, China-Japan Friendship Hospital, Beijing, China. Electronic address: [email protected].
PMID: 41819485 DOI: 10.1016/j.neuropharm.2026.110923
Abstract

Defective Mitophagy plays key roles in mitochondrial dysfunction, inflammation, and energy deprivation, and this defect can lead to synaptic loss and cognitive decline in Alzheimer's disease (AD). Although pharmacological enhancement of Mitophagy has been found to ameliorate cognitive impairment in AD models, therapeutic strategies directly targeting this pathway remain limited. Ajugol, a bioactive iridoid glycoside isolated from Rehmannia glutinosa, has recently been identified as a potential metabolic regulator. In this study, we demonstrated that ajugol markedly alleviates mitochondrial damage and Mitophagy impairment in 5 × FAD mice and HT22 cells. Mechanistically, ajugol upregulates BCL2-interacting protein 3 (BNIP3), which recruits LC3 to damaged mitochondria, thereby promoting mitophagosome formation and ultimately contributing to improved cognitive function. Notably, Bnip3 knockdown in hippocampal neurons abolished the beneficial effects of ajugol in 5 × FAD mice, exacerbating Mitophagy defects and mitochondrial dysfunction, ultimately impairing cognitive performance. These findings highlight a previously unrecognized mechanism by which ajugol mitigates amyloid pathology, synaptic dysfunction, and cognitive decline in 5 × FAD mice and HT22 cells by enhancing BNIP3-mediated Mitophagy, providing a potential therapeutic strategy for AD intervention.

Keywords

Ajugol; Alzheimer's disease; BNIP3; Cognitive decline; Mitophagy.

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