Polygonatum sibiricum polysaccharide ameliorates neurotoxicity in Alzheimer disease mice by inhibiting endoplasmic reticulum stress and lipid raft formation through AMPK/GSK3β/Nrf2 pathway.

Polygonatum sibiricum polysaccharide (PSP) is known for its anti-inflammatory and cognitive improvement effects. However, its potential to alleviate neurotoxicity in Alzheimer's diseafse (AD) has not been thoroughly explored. This study aims to investigate the effects of PSP on AD and clarify its underlying mechanisms. Behavioral tests were conducted using Y-maze and Morris water maze in SAMP8 and SAMR1 mice. Histopathological changes were assessed via ThT and TUNEL staining. Immunofluorescence co-localization and ELISA measured amyloid β-protein (Aβ) levels and inflammatory cytokines. Microglia and astrocyte activation were detected by immunohistochemistry. Oxidative stress and the AMPK/GSK3β/Nrf2 pathway were examined through Western blot. SAMP8 mice exhibited impaired learning and memory, significantly improved by PSP. PSP reduced amyloid plaque load, neuroinflammation, microglia/astrocyte activation, oxidative stress, and neuronal apoptosis in SAMP8 mice. PSP inhibited Aβ production and lipid raft formation in the endoplasmic reticulum-mitochondrial membrane. Activation of the AMPK/GSK3β/Nrf2 pathway was observed, with AMPK inhibition reducing PSP's protective effects. PSP alleviates neurotoxicity in AD model mice by inhibiting ER stress and lipid raft formation via the AMPK/GSK3β/Nrf2 pathway.