Beneficial effects of the herbal medicine zuo gui wan in a mice model of Alzheimer's disease via Drp1-Mediated inhibition of mitochondrial fission and activation of AMPK/PGC-1α-regulated mitochondrial bioenergetics.

ETHNOPHARMACOLOGICAL RELEVANCE

Zuo Gui Wan (ZGW) is a well-known traditional Chinese medicine decoction used for approximately 400 years to treat age-related degenerative conditions, including cognitive impairment in older adults, osteoporosis, and general aging. However, the mechanism of action for ZGW remains unclear.

AIMS OF THE STUDY

This study aims to investigate the efficacy of ZGW in improving cognitive function in Alzheimer's disease (AD) animal models and to explore the underlying mechanisms, presenting a novel perspective in the field.

MATERIALS AND METHODS

Six-month-old male APP/PS1 mice were divided into three groups that received either metformin (200 mg/kg daily) or ZGW (6 and 12 g/kg daily). High-performance liquid chromatography was conducted for ZGW's quality control. Cognitive function was assessed using the Morris water maze test. Neuronal loss, synaptic plasticity, and β-amyloid (Aβ) deposition were evaluated through Western blot or immunofluorescence staining. The underlying molecular mechanisms were investigated using ELISA, Western blot, qRT-PCR, co-immunoprecipitation assay, ATP assay, and cytochrome c oxidase assay.

RESULTS

ZGW, administered in both low and high doses, significantly enhanced cognitive performance, notably decreased neuronal loss and Aβ deposition, and reduced levels of Aβ1-40/42. It also inhibited excessive mitochondrial division primarily by suppressing phosphorylated dynamin-related protein 1 (Drp1), especially at high doses of ZGW. Co-immunoprecipitation experiments further confirmed that ZGW inhibited the interaction between Aβ and p-Drp1. Furthermore, similar to the effects of the AMP-activated Protein Kinase (AMPK) activator metformin, ZGW led to a marked increase in the mitochondrial DNA copy number and upregulated the AMPK/PGC-1α/NRF1/TFAM pathway. Improvements in mitochondrial function were evident from the increased ATP production, elevated expression of superoxide dismutase 2, and upregulated cytochrome c oxidase activity. Additionally, the excess byproduct of reactive oxygen species, 4-hydroxy-2-nonenal, decreased in the group treated with ZGW.

CONCLUSION

This study provides compelling evidence that ZGW improves cognitive impairment in APP/PS1 mice by activating AMPK/PGC-1α-regulated mitochondrial bioenergetics and inhibiting Aβ-induced mitochondrial fragmentation, highlighting its potential as an effective therapeutic strategy for AD.