Regulation of STING G-quadruplex for rescuing cellular senescence and Aβ phagocytic capacity of microglia

Abstract

Alzheimer's disease (AD), the most common form of dementia, affects millions of people worldwide and its cause is very complicated. Besides the classical amyloid cascade hypothesis, oxidative stress, metal ion imbalance, cellular senescence and neuroinflammation are also considered crucial triggers of AD. Therefore, therapeutic strategies other than inhibiting Aβ deposition are very promising. As a crucial innate immune pathway, the abnormal activation of the cGAS-STING pathway in AD has attracted much attention and become a promising target for AD treatment. Here, we identify a highly conserved and stable G-quadruplex (G4) in the STING promoter region, and further verify its function in transcriptional inhibition of STING by using CRISPR technology to precisely target STING G4. Intriguingly, down-regulation of STING expression can alleviate cellular senescence and restore the Aβ phagocytic capacity of microglia. Our results highlight the compelling therapeutic potential of STING promoter G4 for regulation of the abnormal activation of the cGAS-STING pathway in AD. Different from the existing therapeutic strategies for AD, this work provides an alternative way of targeting the functional gene secondary structure, such as the STING promoter region, which may promote the design and synthesis of drug candidates for AD.