Identification of Flavonoid Compounds in Treating Alzheimer’s Disease Based on Network Medicine Framework Strategy

Alzheimer's disease (AD) currently lacks effective therapeutics, but blood-brain-barrier-penetrating flavonoids show promising therapeutic potential. To address this critical need, we employed a novel network medicine framework to systematically identify flavonoid compounds for AD therapy by quantifying their network proximity to AD targets. Our systematic screening identified 48 potential anti-AD flavonoids, of which luteolin, quercetin, apigenin (API), and baicalein demonstrated significant neuroprotective effects in A[Formula: see text]25-35-induced rat pheochromocytoma (PC12) cell models. Of these, API emerged as the most promising candidate. A network pharmacological analysis revealed that API likely exerts its anti-AD effects through modulating apoptosis and inflammatory response, and AKT1 and NFKBIA were identified as key therapeutic targets. Experimental validation demonstrated that API treatment impeded the H₂O₂-induced decline in the mitochondrial membrane potential of PC12 cells, suppressed apoptosis, and mitigated neuronal damage. Furthermore, API downregulated the AKT/NF-[Formula: see text]B signal pathway, promoted microglial M2 polarization, and attenuated LPS-induced neuroinflammation in BV2 cells. API also alleviated the toxic effects of M1 microglia on neurons. This network-based screening strategy provides an innovative approach for developing new AD therapeutics.