Codonopsis pilosula polysaccharides alleviate neuronal apoptosis induced by endoplasmic reticulum stress-activated PERK-ATF4-CHOP signaling in APP/PS1 mice

Background Codonopsis polysaccharides (CPPs) shows neuroprotective potential in Alzheimer's disease (AD) and may reduce neuronal apoptosis by modulating endoplasmic reticulum stress (ERS). Objective To investigate the protective mechanisms of CPPs against neuronal apoptosis in APP/PS1 mice, focusing on the ERS response and the PERK-ATF4-CHOP signaling pathway. Methods APP/PS1 mice were orally administered CPPs at different doses. Their learning and memory abilities were evaluated using the Morris water maze (MWM). The integrity of hippocampal neurons and senile plaque deposition were assessed using histopathology, immunohistochemistry, and immunofluorescence. The expression of amyloid-β (Aβ) plaques secretase protein, ERS markers, and apoptosis-related proteins was assessed using western blot analyses. The affinity of the PERK-ATF4-CHOP pathway and CPPs was analyzed and assessed using molecular docking. Results MWM testing revealed that CPPs improved the learning and memory abilities of APP/PS1 mice. Histopathological examination confirmed that CPPs reduced hippocampal neuronal apoptosis. Immunohistochemistry and immunofluorescence analysis showed that CPPs decreased Aβ protein expression and ERS. Western blot analysis further confirmed that CPPs reduced the expression of proteins related to Aβ synthesis; downregulated the expression of glucose-regulated protein 78 (GRP78), PERK, ATF4, CHOP, and Bcl-2 associated X protein (Bax), while upregulating the expression of B-cell lymphoma 2 (Bcl-2). Conclusions This study demonstrates that CPPs exert neuroprotective effects by targeting the PERK-ATF4-CHOP signaling pathway and alleviating ERS, suggesting a novel approach and potential therapeutic agent for AD treatment.