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

Abstract

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.