One amino acid on one protein. That is where Scripps Research scientists say a good part of the brain inflammation in Alzheimer’s disease comes down to.
The protein is called STING. Normally it works as an early-warning system for the immune system. Inside Alzheimer’s brains, the team found, STING undergoes a chemical change called S-nitrosylation, or SNO, which involves sulfur, oxygen and nitrogen. The change pushes STING into overdrive. Cell Chemical Biology published the study on April 23, 2026.
Pinning down the spot
Stuart Lipton, a clinical neurologist and the senior author, discovered S-nitrosylation more than 30 years ago. In that process a nitric oxide relative binds a cysteine in a protein and alters how it works. Aging, inflammation and pollutants, air pollution and wildfire smoke among them, can set it off.
Postdoctoral researcher Lauren Carnevale led the effort in Lipton’s lab, working with mass spectrometry expert John Yates III. Together they located the exact site on STING: cysteine 148. Once that residue carries the SNO tag, STING bunches into bigger complexes and inflammation follows.
The tagged form, SNO-STING, was abundant in three places: autopsy brain tissue from Alzheimer’s patients, cultured human brain immune cells that had been exposed to Alzheimer’s proteins, and a mouse model of the disease.
A cycle that feeds itself
Lab experiments added a twist. The protein clumps tied to Alzheimer’s, amyloid-beta and alpha-synuclein among them, can start the reaction in STING themselves. The researchers suggest the result is a loop. Protein clumps, together with aging and environmental influences, produce inflammation that generates nitric oxide. That drives S-nitrosylation of STING, which drives more inflammation.
To test the idea, the team engineered a version of STING with no cysteine 148, so it could not be modified. In the mouse model, brain immune cells carrying it showed significantly less inflammation. The synapses, the connections between nerve cells, were protected from degradation. Holding on to synapses tracks with resisting the mental decline of dementia.
“This is a new and important therapeutic target for Alzheimer’s disease,” Lipton said. He pointed out one reason it looks promising: “You still need STING to protect yourself from infections, and when we target cysteine 148, we’re not blocking the entire molecule; we’re just preventing STING from becoming overactivated.”
Early days
The study was preclinical, carried out in human cells, brain samples and mice. Lipton’s group is now working to develop small molecules that block cysteine 148, with plans to test them in preclinical models. The National Institutes of Health and the U.S. Department of Defense/U.S. Department of the Army supported the work in part.
Sources
- Chemical Reaction Sparks Alzheimer's Brain Inflammation – Mirage News (Scripps Research release)
- Unlocking the Neuroinflammatory Cascade: Scripps Research Identifies Critical Molecular Switch – LabQ
