Neurodegenerative conditions are clearly associated with the chronic inflammation of aging. Unresolved inflammatory signaling is harmful to tissue structure and function, and a broad range of evidence points to dysregulated immune cell function in the brain as an important contribution to pathology. Inflammatory signaling is complex, however, and finding ways to intervene in unwanted sustained inflammatory reactions that do not also sabotage normal necessary short-term inflammatory reactions has so far proven to be challenging. Here, researchers focused on a well-studied innate immune regulator of inflammation, STING, and show that disabling it can reduce both inflammation in the brain and the progression of Alzheimer's pathology in a mouse model of the condition.
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 STING 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.
Link: https://doi.org/10.1002/alz.70305
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