Exploration of the pharmacological components and therapeutic mechanisms in treatment of Alzheimer's disease with Polygonati Rhizoma and its processed product using combined analysis of metabolomics, network pharmacology, and gut microbiota.

Polygonati Rhizoma (PR, Huangjing in Chinese) and its processed product (PRP), which are used in Traditional Chinese medicine (TCM) for cognitive enhancement and treatment of Alzheimer's disease (AD), have not been fully explored in terms of the different mechanisms underlying their anti-AD effects. Therefore, we used APP/PS1 mice as an AD model to assess the effects of PR and PRP on anxiety-like behaviors, cognitive function, memory performance, and pathological changes in the murine brain. UPLC-HRMS was applied to identify the components of PR and PRP that entered into the blood and brain. Network pharmacology was used to elucidate potential mechanisms underlying the improvement of AD. Differences in the intestinal flora composition between mice treated with PR and PRP were investigated using 16S rRNA sequencing, establishing a correlation between pharmacological components and distinct flora profiles. The results revealed that both PR and PRP interventions ameliorated cognitive deficits and attenuated Amyloid β (Aβ) plaque deposition in the brains of AD mice. Seven specific blood-entering components, namely glutamic acid, Phe-Phe, and uridine, etc., were associated with PR intervention, whereas ten specific blood-entering components including (2R,3S)-3-isopropylmalate, 3-methylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione, and 3-methoxytyrosine were related to PRP intervention. Uridine was identified as a common brain-penetrating component in both PR and PRP interventions. Network pharmacology analysis suggested that the NOD-like receptor signaling pathway, Calcium signaling pathway and Alzheimer's disease were specific pathways targeted in AD treatment using PR intervention. Moreover, the apoptosis pathway was specifically linked to AD treatment during PRP intervention. Furthermore, the administration of both PR and PRP enhanced the abundance and diversity of the intestinal flora in APP/PS1 mice. Western blotting confirmed that PR excels in regulates inflammation, whereas PRP balances autophagy and apoptosis to alleviate the progression of AD. This study offers valuable insights and establishes a robust foundation for further comprehensive exploration of the intrinsic correlation between TCM and AD.