STING deletion protects against amyloid β-induced Alzheimer's disease pathogenesis

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.

To investigate a role for the key innate immune adaptor molecule, stimulator of interferon genes (STING), in AD, we deleted Sting1 in the 5xFAD mouse model of AD-related amyloidosis and evaluated the effects on pathology, neuroinflammation, gene expression, and cognition.

Genetic ablation of STING in 5xFAD mice led to improved control of amyloid beta (Aβ) 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 characterized by reduced expression of type I interferon signaling genes in both microglia and excitatory neurons.

These findings reveal critical roles for STING in Aβ-driven neurological disease and suggest that STING-targeting therapeutics may offer promising strategies to treat AD.

Stimulator of interferon genes (STING) deficiency in the 5xFAD mouse model of Alzheimer's disease-related amyloidosis results in decreased amyloid beta (Aβ) deposition and altered microglial activation status. Protection against amyloidosis in STING-deficient 5xFAD mice is associated with decreased expression of genes involved in type I IFN signaling, improved neuronal health, and reduced levels of oxidative stress. Loss of STING in 5xFAD mice leads to improved spatial learning and memory.