Ginseng and Polygonum multiflorum formula protects brain function in Alzheimer's disease

Jingjing Liu ¹ Feng Wei ² Ya-dan Wang ² Jing Liu ² Beilei Xu ³ Shuang-cheng Ma ^1* Jian-bo Yang ²

• ¹ Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing Municipality, China
• ² National Institutes for Food and Drug Control (China), Beijing, Beijing Municipality, China
• ³ School of Pharmacy, Harbin University of Commerce, Harbin, Heilongjiang Province, China

Background:Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no effective treatment. The Panax ginseng C.A.Mey. and Polygonum multiflorum Thunb. formula (GSPM) has shown potential neuroprotective effects, but its therapeutic efficacy and mechanisms in AD remain unclear.Methods:SAMP8 mice, an AD model, were treated with GSPM (low: 117 mg/kg, high: 234 mg/kg) or donepezil (1.3 mg/kg) via gavage for 2 months. Cognitive function was assessed by the Morris water maze. Hippocampal morphology was evaluated with H&E staining, and neuronal apoptosis was detected using TUNEL. Microgliosis and astrogliosis were analyzed by Iba1 and GFAP immunohistochemistry. Levels of phosphorylated Tau, Aβ1-42, Aβ1-40, inflammatory cytokines, oxidative stress markers, and senescence markers were measured. Gut microbiota was analyzed by 16S rRNA sequencing. In vitro, GSPM's effects on Aβ1-42-stimulated HT22 neurons were evaluated. Cell viability was assessed by CCK-8, and apoptosis was detected by flow cytometry. The AMPK/Sirt1 pathway was investigated by Western blotting, and SIRT1-dependent effects were evaluated after EX527 treatment.Results:GSPM treatment improved cognitive function, reduced hippocampal damage, and decreased neuronal apoptosis in AD mice. It alleviated neuroinflammation by reducing microgliosis and astrogliosis and lowered the levels of p-Tau and Aβ in the hippocampus and cerebrospinal fluid. GSPM also reversed inflammation, oxidative stress, and neuronal senescence in AD mice. Additionally, GSPM modulated gut microbiota composition by reducing microbial diversity and restoring the Firmicutes/Bacteroidetes ratio to control levels. GSPM increased Lactobacillus abundance, which was negatively correlated with inflammation, Aβ1-42, p-Tau, and senescence markers, while decreasing bacteria like Oscillibacter, Helicobacter, and Odoribacter associated with inflammation and senescence. In vitro, GSPM increased cell viability, reduced apoptosis, and alleviated oxidative stress in Aβ1-42-stimulated HT22 neurons. It decreased pro-inflammatory cytokines and senescence markers. Moreover, GSPM restored AMPK phosphorylation and Sirt1 expression in neurons, and Sirt1 inhibition by EX527 reversed GSPM's neuroprotective effects.Conclusion:GSPM protects against AD by suppressing inflammation, oxidation, and senescence, potentially via the Sirt1 signaling pathway, offering a novel therapeutic approach for AD.