2024 

Blockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer’s disease pathologies

https://www.nature.com/articles/s12276-024-01295-y

In mammalian cells, ectopic DNA activates the cGAS-STING pathway to trigger the innate immune response. Double-stranded nucleic acids longer than 45 base pairs activate cGAS to produce cyclic 2’-3’-GMP-AMP (cGAMP), the physiological ligand of STING12. STING is activated by a variety of cyclic dinucleotides and induces noncanonical autophagy and downstream immune signaling. Tank-binding kinase 1 (TBK1), which is directly recruited by STING, sequentially phosphorylates interferon-regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) to trigger the expression of type I interferon (IFN), IFNβ, and inflammatory cytokines, including TNF-α and CXCL10. 

Autocrine and paracrine type-I-IFN responses foster tissue resistance to viral infection. This process is mediated by IFNAR1/2 and Janus kinase 1 (JAK1)- signal transducer and activator of transcription 1 (STAT1) signaling. The cGAS-STING pathway is known to protect organisms from microbial threats by triggering a broad spectrum of immune responses13. 

Notably, cGAS recognizes nucleic acids in a sequence-nonspecific manner and can thus be adversely activated by endogenous nuclear and mitochondrial DNA (mtDNA) under certain conditions4,12. The pivotal roles of the cGAS-STING pathway in the DNA damage response, senescence, antiviral response, and cancer have been highlighted14. However, increasing evidence implicates dysregulation of the cGAS-STING pathway in neurological disorders, including multiple sclerosis15, Parkinson’s disease16, amyotrophic lateral sclerosis (ALS)17, Huntington’s disease18, and recently, amyloidosis19 and tauopathy20.

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