STING deletion protects against amyloid beta-induced Alzheimer's disease pathogenesis. Mus musculus

INTRODUCTION: While immune dysfunction has been increasingly linked to Alzheimer's disease (AD) progression, many major innate immune signaling molecules have yet to be explored in AD pathogenesis using genetic targeting approaches. METHODS: To investigate a role for the key innate immune adaptor molecule STING in AD, we deleted it in the 5xFAD mouse model of AD-related amyloidosis and evaluated the effects on pathology, neuroinflammation, gene expression, and cognition. RESULTS: Genetic ablation of STING in 5xFAD mice led to improved control of amyloid beta plaques, alterations in microglial activation status, decreased levels of neuritic dystrophy, and protection against cognitive decline. Moreover, rescue of neurological disease in STING-deficient 5xFAD mice was associated with reduced expression of type I interferon signaling genes in both microglia and excitatory neurons. DISCUSSION: Theses findings reveal critical roles for STING in amyloid beta-driven neurological disease and suggest that STING-targeting therapeutics may offer promising strategies to treat AD.