Mechanism of Atractylodis Rhizoma in improving cognitive dysfunction in Alzheimer's disease by regulating the cAMP/CREB/BDNF pathway.

BACKGROUND

Alzheimer's disease (AD) is a progressive, debilitating condition with substantially limited therapeutic options. Atractylodis Rhizoma, a spleen-invigorating herb in Traditional Chinese Medicine (TCM), shows promise for AD, but its mechanisms are unknown.

METHODS

Chemical constituents of the ethanol extract of Atractylodis Rhizoma (EEAR) were identified via UHPLC-HRMS and followed by network pharmacology integrated with molecular docking to predict putative therapeutic targets. An AD rat model was established by bilateral intracerebral stereotaxic injection of Aβ₂₅-₃₅. Cognitive function and neuronal damage were evaluated using behavioral tests and Nissl staining. Levels of key pathway components were measured by ELISA, RT-qPCR, and Western blotting, and inflammatory factors were measured by ELISA. RNA sequencing (RNA-Seq) and in vitro experiments were conducted to validate EEAR's regulatory effects on the key signaling pathway.

RESULTS

EEAR administration ameliorated cognitive deficits and attenuated hippocampal neuronal damage in AD rats. Notably, EEAR markedly reduced the concentrations of IL-6, IL-1β, and TNF-α in the rat hippocampus, concomitant with upregulation of the cAMP/CREB/BDNF signaling pathway. RNA-seq analysis confirmed significant enrichment of DEGs in the cAMP signaling pathway in the EEAR-H. In vitro, EEAR protected HT22 cells against Aβ₂₅-₃₅-induced injury, and the CREB-specific inhibitor KG-501 effectively blocked EEAR-induced activation of the cAMP/CREB/BDNF pathway.

CONCLUSION

EEAR mitigates AD pathogenesis by directly targeting hippocampal neuroinflammation and potently activating cAMP signaling, establishing its potential as a multi-target therapeutic candidate and providing a scientific basis for traditional medicine-derived AD interventions.