Icariin, a natural flavonoid glucoside, inhibits neuroinflammation in mice with triple-transgenic Alzheimer’s disease by regulating the Akt/GSK-3β signaling pathway

• ICA enhances learning and memory abilities and alleviates AD pathology in AD models. • ICA inhibits astrocyte-mediated neuroinflammation via the Akt/GSK-3β pathway. • ICA regulates lncRNAs such as Meg3 and Malat1 , which may represent a novel strategy. Icariin (ICA), a natural flavonoid glucoside from traditional Chinese medicine, possesses various pharmacological properties such as anti-inflammatory, anti-aging, and neuroprotective effects. Recent studies suggest its potential in treating Alzheimer’s disease (AD). However, the exact mechanisms of how ICA modulates neuroinflammation in AD remain unclear. In this study, oral ICA administration improved cognitive function in mice, decreasing escape latency in behavioral tests and altering protein levels related to AD pathology, including boosting acetylcholine and reducing p-tau/tau and acetylcholinesterase. Additionally, in 3 × Tg-AD mice, ICA therapy inhibited microglia and astrocyte activation and reduced inflammatory cytokines (IL-1β, TNF-α, IL-6) at the protein level. RNA-seq analysis revealed decreased expression of Nrxn3 , Meg3 , and Malat1 genes in 3 × Tg-AD animals treated with ICA. Furthermore, ICA activated the Akt/GSK-3β signaling pathway, known for its role in neuroinflammation, suggesting a potential mechanism by which ICA suppresses inflammation. This study proposes Meg3 and Malat1 lncRNA as therapeutic targets against AD, offering a novel approach for combating neuroinflammation in AD through the inhibition of the Akt/GSK-3β pathway.