Preparation, activity, and mechanistic insights of processed Polygala tenuifolia glycoprotein in ameliorating Alzheimer's disease.

This study examined the efficacy and mechanism of Polygala tenuifolia glycoprotein (ZPG) in alleviating Alzheimer's disease (AD) for clinical application. ZPG's effects were tested in scopolamine hydrobromide-induced AD mice using behavioral, histological, and biomarker investigations. Additionally, 16S rDNA sequencing and lipidomics revealed ZPG's impact on gut microbiota and lipid metabolism, supported by pathway enrichment and correlation analyses. JNK pathway modulation was studied in vitro with purified and characterized ZPG-2. Results showed ZPG significantly improved cognitive deficits, reduced hippocampal pathology, and normalized APP, p-JNK, bax, and bcl-2 levels in AD mice. It also modulated gut microbiota and lipid metabolism, particularly glycerophospholipid pathways. ZPG-2 exhibited neuroprotective effects in Aβ25-35-induced PC12 cells by reducing apoptosis, inhibiting LDH release, and regulating oxidative stress and JNK activity. Structural analysis identified ZPG-2 as a 26 kDa glycoprotein with an O-linked glycopeptide bond and random coil conformation. Correlation analysis showed significant gut microbiota-AD biomarker relationships. These findings suggest ZPG may alleviate AD by reducing oxidative stress, inhibiting apoptosis, modulating gut microbiota, enhancing lipid metabolism, and suppressing the JNK signaling pathway. ZPG may be medicinal, however, more research is needed to validate its efficacy and mechanisms. This study lays the foundation for ZPG as an AD therapy for the future.