A Mechanism Linking Protein Aggregation to STING Activation and Inflammation in the Aging Brain
Inflammation in the brain is thought to be important in the progression of neurodegenerative conditions, disruptive to cell and tissue function. Understanding why the other features of neurodegenerative disease activate chronic inflammation in the brain is a necessary first step on the long road to the development of therapies capable of selectively suppressing this harmful inflammation while only minimally interfering in the normal, necessary inflammatory response to pathogens and injury.
The protein called STING normally functions as part of the immune system's early-warning system. In the brains of people with Alzheimer's, the team discovered that STING undergoes a chemical modification known as S-nitrosylation (or SNO, a reaction involving sulfur, oxygen, and nitrogen) that promotes its overactivation. Blocking this chemical change to STING in a mouse model of the disease decreased neuroinflammation.
Over three decades ago researchers discovered the S-nitrosylation process, in which a molecule related to nitric oxide (NO) binds to a cysteine amino acid in proteins, producing "SNO" and thus regulates the protein's function. SNO, which can be triggered by aging, neuroinflammation, and environmental toxins such as air pollution and wildfire smoke, disrupts a variety of different proteins in the body.
In this new study, the team focused on the protein STING, which was previously linked to Alzheimer's inflammation. They pinpointed exactly where on STING an S-nitrosylation reaction occurred, homing in on one specific building block of the protein: cysteine 148. When cysteine 148 is S-nitrosylated, they discovered, STING clusters into larger complexes and triggers inflammation. The team found high levels of the chemically modified form of STING (called SNO-STING) in postmortem brain tissue from Alzheimer's patients, in human brain immune cells grown in the lab and exposed to Alzheimer's proteins, and in a mouse model of the disease.
In laboratory experiments, the team showed that the clumps of proteins found in the brain in Alzheimer's - including amyloid-beta and alpha-synuclein - can themselves trigger the S-nitrosylation reaction in STING. This finding suggests that inflammation occurs in a cycle: initial protein clumps, coupled with environmental influences and aging, could cause inflammation that generates NO, driving S-nitrosylation of STING, which in turn drives more inflammation.
The researchers then engineered a version of STING lacking cysteine 148 so it couldn't be S-nitrosylated. When this modified protein was introduced into a mouse model of Alzheimer's, brain immune cells showed significantly less inflammation, and critically, the connections between nerve cells (called synapses) were protected from degradation. This preservation of synapses is known to correlate with protection from the cognitive decline of dementia.
Link: https://www.scripps.edu/news-and-events/press-room/2026/20260423-lipton-alzheimers.html