Apelin-13, a neuropeptide, has been recognized for its neuroprotective properties. Our previous study found apelin-13 improves cognitive function in Alzheimer’s disease (AD) rats by inhibiting neuroinflammation through upregulation of BDNF/TrkB signaling pathway. However, the precise mechanism by which apelin-13 modulates BDNF remains unclear. Thus, this study aimed to unravel the specific regulatory mechanism by which apelin-13 regulates BDNF. Bilaterally intracerebroventricular injection with Aβ25–35 was used to establish an in vivo model of AD. For the generation of METTL3 KO rats, the Crispr/Cas9 method was applied. PC12 cells were treated with Aβ25–35 to establish an in vitro model of AD. The cognitive function of the rats was evaluated with the Morris water maze and the novel object recognition test. Hippocampal damage and neuron loss were detected through H&E and immunofluorescent staining. METTL3, BDNF, TrkB, and p-TrkB were examined by Western blotting. Inflammation-related cytokines, IBA1, GFAP, IL-1β, and TNF-α were detected by Western blotting, immunofluorescent staining, ELISA, and qRT-PCR. m6A modification level was evaluated through MeRIP. A flow cytometer was applied to evaluate cell apoptosis. Cell proliferation was examined using MTT. m6A methylation inhibitor DAA reverses the improvement effect of apelin-13 on cognitive function, hippocampal nerve damage, neuron loss, and neuroinflammation in Aβ25–35-treated rats. Further results showed that apelin-13 upregulated METTL3, BDNF-AS m6A methylation, inhibited BDNF-AS expression, and subsequently upregulated BDNF/TrkB signaling pathway and reduced neuroinflammation in in vivo and in vitro AD models in a dose-dependent manner. Knockdown of METTL3 abolished apelin-13’s improvement effect in AD rats. Apelin-13-mediated upregulation of METTL3 enhances neuroinflammation inhibition and BDNF/TrkB signaling pathway via m6A-dependent downregulation of lncRNA BDNF-AS, thus ameliorating AD. Our study offers novel insights into the pathogenesis of AD and identifies potential drug targets for its treatment.

Objective: To elucidate the molecular targets and mechanisms by which Acorus tatarinowii exerts therapeutic effects in major depressive disorder (MDD) using network pharmacology and molecular docking approaches. Methods: Bioactive compounds of Acorus tatarinowii were identified from comprehensive pharmacological databases. MDD-related targets were sourced from extensive genomic repositories. Overlapping targets were determined and subjected to network topology and protein–protein interaction (PPI) analyses to identify core targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to reveal pertinent biological processes and signaling pathways. Molecular docking simulations validated the interactions between key bioactive compounds and core targets. Results: A total of 57 bioactive compounds were identified in Acorus tatarinowii, including apigenin, heterotropan, and isoelemicin. Integrative analysis revealed 700 compound-related targets and 2590 MDD-associated targets, with 150 intersecting targets. Network analyses pinpointed five core targets: TP53, STAT3, AKT1, PIK3CA, and PIK3R1. GO enrichment identified 858 significant biological processes, while KEGG pathway analysis highlighted 155 enriched pathways, notably the PI3K-Akt, cAMP, and MAPK signaling pathways. Molecular docking studies demonstrated strong binding affinities between key compounds and their respective targets. Conclusions: This study delineates the multifaceted polypharmacological mechanisms through which Acorus tatarinowii may confer protective effects against major depressive disorder, underscoring its potential as a promising therapeutic agent.