Removing a key immune signaling gene in mice could reduce Alzheimer’s disease–related brain changes and improve cognitive performance, according to new research.
In the study, researchers focused on the stimulator of interferon genes (STING), a protein that triggers immune responses in the brain. Genetically deleting STING in mice with Alzheimer’s disease–like pathology led to lower amyloid beta plaque buildup, reduced inflammation, and improved memory.
Alzheimer’s disease is marked by the accumulation of amyloid beta proteins, which form plaques that damage brain cells. While the immune system’s role in Alzheimer’s disease is established, the specific function of STING had not been fully tested in live models.
To investigate, the researchers used the 5xFAD mouse model, which carries human genes that cause amyloid buildup. These mice were bred with STING knockout mice to create a strain called 5xStKO. The researchers then compared the effects of STING deletion in 5xStKO mice with standard 5xFAD controls.
Mice lacking STING had fewer and smaller amyloid plaques in the cortex, hippocampus, and subiculum. ELISA tests confirmed significantly lower levels of both soluble and insoluble amyloid beta 42.
The benefits extended beyond plaque reduction. STING-deficient mice had fewer activated microglia—the brain’s immune cells involved in Alzheimer’s disease–related inflammation. These microglia also expressed fewer inflammatory markers and maintained a resting, or homeostatic, morphology.
Single-nuclei RNA sequencing revealed that STING-deficient microglia and excitatory neurons had reduced expression of interferon-related and antiviral response genes. In contrast, genes linked to synaptic health, calcium signaling, and cognitive function were more active in neurons lacking STING.
Neuronal damage markers also improved. Mice without STING had fewer dystrophic neurites along with reduced oxidative stress and lower rates of neuronal cell death in the hippocampus.
These biological changes were matched by behavioral improvements. In Morris water maze tests, STING-deficient mice located the hidden platform more quickly and spent more time in the correct quadrant during memory recall, indicating better spatial learning and memory retention.
The findings suggested that STING signaling could contribute to Alzheimer’s disease pathology and cognitive decline. Genetic deletion of STING led to improvements in amyloid clearance, immune activation, and neuronal health in this mouse model.
Further studies are needed to determine which cell types are most affected by STING and whether pathways like vesicle trafficking or lysosomal stress may activate STING independently of DNA sensing. These insights could help develop targeted treatments that inhibit STING in the brain while preserving immune functions elsewhere in the body.
The authors declared no conflicts of interest.
Source: Alzheimer's & Dementia