Icariin alleviates cognitive dysfunction by reducing neuroinflammation via the cGAS-STING pathway

Epimedium brevicornu Maxim, a Chinese herbal medicine, is known for its efficacy in nourishing the kidneys. Icariin (ICA), the primary active ingredient in Epimedium brevicornu Maxim., possesses multiple pharmacological properties, yet its impact on Alzheimer's disease (AD) warrants further exploration.

Study aims to explore the inhibitory impact of ICA on neuroinflammation in AD via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.

SPF-grade male ICR mice were used to establish an AD model by lateral ventricle injection of Aβ_1-42. Behavioral, pathological assessments, as well as immunofluorescence staining, molecular docking, and Western blot analyses, were conducted to evaluate the effects of ICA treatment on memory function, neuronal damage, neuroinflammation, and the cGAS- STING pathway in mice.

ICA significantly improved memory impairment, alleviated neuronal damage and apoptosis, and suppressed neuroinflammation in AD mice. Additionally, ICA inhibited microglial hyperactivation, promoting the transition from the M1 to the M2 phenotype. It specifically inhibited the activation of the cGAS-STING pathway and down-regulated the expression of cGAS, STING, p-TBK1/TBK1, p-IRF3/IRF3 and p-NF-κB/NF-κB. Furthermore, molecular docking revealed that the binding energy between ICA and cGAS was -7.07 kcal/mol, indicating a stable interaction. Further validation using the cGAS-selective small molecule inhibitor RU.521 confirmed the protective effects of ICA against cGAS-STING signaling on microglial transformation and neuroinflammation.

ICA exhibits therapeutic potential in AD by inhibiting microglial transformation and neuroinflammation through the cGAS-STING pathway, positioning it as a candidate drug for AD treatment targeting this pathway.