For families watching a parent or spouse lose their memory, the question is always the same: what is actually going wrong inside the brain? Researchers at Scripps Research now have a concrete part of the answer, and it comes down to one protein and one spot on it.
The protein is called STING. In a healthy body it serves as part of the early-warning system against threats. In Alzheimer’s disease, the team reported in Cell Chemical Biology, STING picks up a chemical modification known as S-nitrosylation, or SNO, and becomes overactive. The brain’s immune cells then stay switched on and keep up a steady inflammation that damages the connections between nerve cells.
Where the damage starts
The researchers worked with human Alzheimer’s brain cells and other experimental models. With postdoctoral researcher Lauren Carnevale leading the group and Scripps Professor John Yates III contributing his mass spectrometry expertise, they found the exact location of the change: cysteine 148, one building block of the protein. When that site is modified, STING gathers into larger complexes that set off inflammation.
They saw high levels of the altered form, called SNO-STING, in postmortem brain tissue from people with Alzheimer’s. It also showed up in human brain immune cells grown in the lab and exposed to Alzheimer’s-related proteins, and in a mouse model of the disease.
The protein clumps tied to Alzheimer’s, including amyloid-beta and alpha-synuclein, can trigger the reaction themselves. So the team suspects a loop. Clumps, aging and environmental factors spark inflammation, the inflammation produces nitric oxide, the nitric oxide modifies STING, and STING fuels more inflammation. Stuart Lipton, the senior author, first described S-nitrosylation more than 30 years ago. His lab has shown it can be set off by aging, inflammation, air pollution and wildfire smoke.
Protecting the connections
To test whether breaking the loop would help, the scientists built a version of STING without cysteine 148, so it could not be modified. In the mouse model, brain immune cells carrying it showed much lower inflammation. The synapses stayed intact. Keeping those connections is strongly associated with protection against the memory loss seen in dementia.
“This is a new and important therapeutic target for Alzheimer’s disease,” said Lipton, a clinical neurologist. “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.” The same pathway was active in human brain samples and in human stem cell-derived models, he said.
Lipton also pointed to what separates this target from broad anti-inflammatory approaches. “You still need STING to protect yourself from infections,” he said. Aiming at cysteine 148 prevents overactivation without blocking the whole molecule.
This is laboratory work, not a treatment. The team is developing small molecules meant to block cysteine 148 and plans to test them in preclinical studies. Funding came in part from the National Institutes of Health and the U.S. Department of Defense and Army.
