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. 2025 Jun 6.
doi: 10.1007/s12035-025-05073-3. Online ahead of print.

Ginsenoside Rg1 Downregulates miR-9-5p Expression to Modulate SIRT1-Mediated Mitochondrial Dysfunction and Ameliorate Alzheimer's Disease

Yunliang Wang #  1 , Xiangyun Sun #  2 , Biao He  1 , Shaowen Yu  3
Affiliations

Ginsenoside Rg1 Downregulates miR-9-5p Expression to Modulate SIRT1-Mediated Mitochondrial Dysfunction and Ameliorate Alzheimer's Disease

Yunliang Wang et al. Mol Neurobiol. .

Abstract

This study aimed to investigate the mechanism of ginsenoside Rg1 in Alzheimer's disease (AD) via miR-9-5p/SIRT1-mediated mitochondrial function. The cognitive function of AD mice was assessed by Morris water maze experiment. The histopathological changes in the CA1 region were observed by H&E staining. TUNEL staining combined with the neuronal marker NeuN was used to detect neuronal apoptosis in hippocampal tissues. Aβ1-42 induced HT-22 cells were used as AD in vitro models. MiR-9-5p expression was detected by qRT-PCR, and SIRT1 protein and autophagy-related proteins (LC3B II/I, Beclin-1) levels were measured by western blot. The binding of miR-9-5p with SIRT1 was predicted and validated. Ginsenoside Rg1 treatment in AD mice reduced miR-9-5p expression, increased SIRT1 level, attenuated mitochondrial dysfunction, and effectively improved AD symptoms in mice, while such effect can be either reversed by miR-9-5p agomir or SIRT1 inhibitor (EX527). In vitro, Aβ1-42-induced HT-22 cell activity was reduced, cell death was significantly increased, and mitochondrial dysfunction was progressed, but treatment of HT-22 cells with Aβ1-42 and ginsenoside Rg1 attenuated mitochondrial dysfunction and improved Aβ1-42-induced HT-22 cell damage. Ginsenoside Rg1 ameliorated Aβ1-42-induced HT-22 cell damage by down-regulating miR-9-5p to regulate SIRT1-mediated mitochondrial dysfunction. miR-9-5p negatively regulates SIRT1. Inhibition of mitochondrial autophagy partially reversed the ameliorative effect of ginsenoside Rg1 on mitochondrial dysfunction and cellular damage in HT-22 cells. Ginsenoside Rg1 down-regulates miR-9-5p expression to modulate SIRT1-mediated mitochondrial dysfunction, hereby attenuating Aβ1-42 induced cell injury in HT-22 cells and alleviating AD in mice.

Keywords: Alzheimer disease; Ginsenoside Rg1; MiR-9-5p; Mitochondrial autophagy; Mitochondrial dysfunction; SIRT1.

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Conflict of interest statement

Declarations. Ethics Approval and Consent to Participate: Animal experiments were reviewed and authorized by the Animal Ethics Committee of The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital). All procedures were carried out in strict accordance with the code of ethics. We had done our utmost to minimize the animal amount and utilized all laboratory procedures to minimize the pain of the mice, including heating pads, sterilization, and fluid supplementation with saline. Consent for Publication: Not applicable. Competing interests: The authors declare no competing interests.

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