Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice

Abstract cGAS senses microbial and host-derived double-stranded DNA (dsDNA) in cytoplasm to trigger cellular innate immune response in a STING-dependent manner. However, it remains unknown whether the cGAS-STING pathway in innate immunity contributes to Alzheimer’s disease (AD). Here we demonstrated the detectable binding of the cGAS-dsDNA in cytoplasm and the activation of microglial cGAS-STING pathway in brains of human AD and aged mice, suggesting a role for the cGAS-STING pathway in this neurodegenerative disease. Cgas −/− ;5×FAD mice were largely protected from cognitive impairment, amyloid-β (Aβ) pathology, neuroinflammation and other sequelae associated with AD. Furthermore, Cgas deficiency in microglia inhibited the conversion of astrocytes into neurotoxic A1 phenotype, and thus alleviated oligomeric Aβ peptides-induced neuronal toxicity. Finally, administration of STING inhibitor H-151 potently suppressed the activation of the cGAS-STING pathway and ameliorated AD pathogenesis in 5×FAD mouse model. In conclusion, our present study has identified a critical molecular link between innate immunity and AD, and suggests that therapeutic targeting of the cGAS-STING pathway activity might effectively interfere with the progression of AD.