Cyclic GMP-AMP synthase (cGAS) is an important nucleic acid sensor in the cytoplasm, which has emerged as a critical mechanism for coupling the sensing of DNA, the binding of cGAS to double-stranded DNA (dsDNA). The binding event allosterically activates cGAS catalytic activity and leads to the production of 2′3′ cyclic GMP–AMP, a second messenger molecule and potent agonist of stimulator of interferon genes (STING). This biochemical cascade eventually induces downstream transcription factors IRF3 and NF-κB mediated production of type I interferon and a variety of inflammatory factors, triggering innate immune response program. 

Previous studies have shown that infection with viral pathogens induces the activation of the cGAS-STING pathway. In this study, the researchers cultured multiple types of primary neural cells and confirmed that the activation of the cGAS-STING pathway occurred mainly in microglia, the resident immune cells in the central nervous system.  

Besides, they found that the cGAS-STING pathway was activated in the brain of patients with AD. The activation of the cGAS-STING pathway had a significant effect on neuroinflammation, microglial phagocytosis, and astrocytic subtyping via Cgas deficiency in 5×FAD mice, a model of AD amyloid pathology. It was demonstrated that a STING inhibitor could suppress neuroinflammatory responses and alleviate AD pathogenesis in 5×FAD mice. 

In summary, this study reveals the critical role of the cGAS-STING pathway in the development and progression of AD, offering a potential targeting for precise AD intervention, and also reveals a new neural innate immune mechanism underly neurodegeneration induced by pathogen infection.