Cordycepin Attenuates Microglial-Mediated Neurotoxicity in Alzheimer's Disease Through Dual Modulation of Pro-Inflammatory and Phagocytic Functions via Caspase1 Suppression and STAT6 Activation

Microglia (MG) play dual roles in Alzheimer’s disease (AD) development. They can worsen the condition by causing inflammation but also help in early stages by removing harmful amyloid-beta (Aβ) through phagocytosis. Consequently, precise modulation of microglial phagocytic activity and inflammatory responses holds considerable significance for AD treatment. Cordycepin (Cor) is a representative active component extracted from Cordyceps militaris, which is a type of medicinal and nutritional food. Although Cor is considered to exert neuroprotective effects, its potential regulatory role in microglial function in AD, as well as the underlying specific mechanisms, remain poorly elucidated. Through transcriptomics combined with <em>in vitro</em> and<em> in vivo</em> experimental validations, we demonstrated that Cor suppresses the pro-inflammatory responses of MG while enhancing their phagocytic capacity for Aβ, with these dual effects mediated through distinct mechanisms. Specifically, on one hand, Cor can activate the STAT6 signaling pathway to upregulate the expression of phagocytosis-related factors, including Arg1, TGFβ, IL10, and CD206, thereby promoting the clearance of Aβ by MG. Notably, activation of the STAT6 signaling pathway does not affect the inflammatory response. On the other hand, Cor can inhibit caspase1 to reduce the levels of inflammation-related factors such as IL1β, TNFα, iNOS, and CD86, thereby alleviating neuroinflammation. Meanwhile, inhibition of caspase1 activity does not impact phagocytic function. This unique dual action of Cor, which simultaneously suppresses inflammation and promotes phagocytosis of MG, opens new avenues for prevention and therapeutic strategies against AD and provides solid experimental evidence and theoretical support.