One building block on one protein. That is where a Scripps Research team says Alzheimer’s brain inflammation gets its start. The protein is STING, the building block is cysteine 148, and blocking a chemical change at that spot calmed inflammation in mice.
The study appeared in Cell Chemical Biology on April 23, 2026. STING normally works as an early-warning system for the immune system. In the brains of people with Alzheimer’s, the researchers found, it gets stuck in overdrive.
The switch
The change is called S-nitrosylation, or SNO, a reaction in which a molecule related to nitric oxide attaches to a cysteine amino acid. Stuart Lipton, the senior author and a clinical neurologist at Scripps, discovered the process more than three decades ago. His lab has linked it to aging, neuroinflammation and environmental toxins such as air pollution and wildfire smoke.
Once cysteine 148 picks up the SNO tag, STING clumps into larger complexes and sets off inflammation. The team found high levels of this modified form, which they call SNO-STING, in postmortem brain tissue from Alzheimer’s patients. They saw it in human brain immune cells grown in the lab and exposed to Alzheimer’s proteins, and in a mouse model of the disease.
The protein clumps that mark Alzheimer’s, including amyloid-beta and alpha-synuclein, can trigger the reaction themselves. That suggests a loop: clumps and aging cause inflammation, inflammation generates nitric oxide, nitric oxide modifies STING, and STING drives more inflammation.
What happened in mice
Postdoctoral researcher Lauren Carnevale led the work in Lipton’s group, together with John Yates III, a mass spectrometry expert at Scripps. They engineered a version of STING with no cysteine 148, so it could not be modified. In the mouse model, brain immune cells carrying that version showed much less inflammation. The synapses, the connections between nerve cells, were protected from breakdown. Synapse preservation is known to track with protection against the cognitive decline of dementia.
“This is a new and important therapeutic target for Alzheimer’s disease,” Lipton said. “It’s exciting to see that blocking this switch in mice reduces inflammation and protects the very brain cell connections that are lost in Alzheimer’s.” He added that the same pathway was active in human Alzheimer’s brain samples and in human stem cell-derived models.
Why the target is narrow
Many anti-inflammatory drugs shut down large parts of the immune system. This approach would not. “You still need STING to protect yourself from infections,” Lipton said, “and when we target cysteine 148, we’re not blocking the entire molecule; we’re just preventing STING from becoming overactivated.”
Lipton’s group is now working on small molecules that block cysteine 148, to be tested in preclinical models. The work was supported in part by the National Institutes of Health and by the U.S. Department of Defense and U.S. Army.
