Picroside II Alleviates the Progression of Alzheimer’s Disease via the NLRP3/Caspase-1/GSDMD Pathway

Alzheimer's disease (AD), an irreversible, degenerative disorder, affects the central nervous system. However, its accurate pathology remains unclear, and studies on treatment modalities are ongoing. Picroside II (PII) is an active compound in the medicinal herb Rhizoma coptis. It has strong effects, including antioxidation, anti-inflammatory, antiapoptotic, and neuroprotective effects. In this study, we analyzed how PII affects cognitive impairment in mice with AD and its underlying mechanism. PII at doses of 20 or 40 mg/kg was given to APP/PS1 mice through intraperitoneal injection for 2 months. Moreover, we carried out the Morris water maze test to evaluate cognitive function. Immunofluorescence analysis was performed to observe cortical Aβ plaque deposition, neuronal loss, and inflammatory cell expression. An enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of the cortical inflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Western blotting and quantitative polymerase chain reaction (qPCR) were performed to measure NLRP3, ASC, GSDMD, and caspase-1 expression. PII improved cognitive function, reduced Aβ plaque deposition and glial activation, and alleviated cortical neuronal loss in APP/PS1 mice. Furthermore, PII decreased the levels of cortical inflammatory factors (TNF-α, IL-6, and IL-1β). In addition, it suppressed NLRP3, ASC, GSDMD, and caspase-1 expression at the mRNA and protein levels. PII enhances the cognitive function of APP/PS1 mice by reducing inflammation and pyroptosis via the suppression of the NLRP3/caspase-1/GSDMD pathway. Therefore, PII is a candidate anti-AD therapeutic agent.