Scientists at Scripps Research have pinned part of the brain inflammation seen in Alzheimer’s disease on a single chemical change to a single protein. The protein is STING, normally part of the body’s early warning system against threats. The study appeared in Cell Chemical Biology.
The brain has its own immune defenses. In Alzheimer’s, growing evidence suggests, those immune cells get stuck in chronic activation and set off ongoing inflammation that damages the connections between brain cells.
The switch
The team found that in Alzheimer’s disease STING undergoes S-nitrosylation, or SNO, a reaction involving sulfur, oxygen and nitrogen. The change appears to make the protein overactive. Lauren Carnevale, a postdoctoral researcher, led the group, which worked with Scripps professor John Yates III, an expert in mass spectrometry. Together they located the exact spot on STING where it happens: a component called cysteine 148. Once that site is modified, STING clumps into larger complexes that switch on inflammatory responses.
Senior author Stuart Lipton discovered S-nitrosylation more than 30 years ago. In the process, a molecule related to nitric oxide attaches to a cysteine amino acid and changes how the protein behaves. His lab has shown that aging, inflammation and environmental exposures such as air pollution and wildfire smoke can trigger it. When large numbers of proteins are hit, the result is what the lab calls a “SNO-STORM”. The phenomenon has been tied to cancer, Parkinson’s disease and Alzheimer’s.
The altered form, SNO-STING, turned up at high levels in postmortem brain tissue from people with Alzheimer’s. It also appeared in human brain immune cells grown in the lab and exposed to Alzheimer’s-related proteins, and in a mouse model of the disease.
A loop that feeds itself
Protein clumps common in Alzheimer’s, including amyloid-beta and alpha-synuclein, can trigger the modification. That suggests a repeating cycle. Aggregates, aging and environmental factors spark inflammation, which produces nitric oxide. The nitric oxide promotes S-nitrosylation of STING, and STING drives still more inflammation.
To break the loop, the researchers engineered a version of STING without cysteine 148, so it could not be modified. In a mouse model of Alzheimer’s, brain immune cells carrying it showed much lower inflammation. The synapses connecting nerve cells were also protected from deterioration, and preserving those connections is strongly associated with protection against cognitive decline.
“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, especially because we found the same pathway to be activated in human Alzheimer’s brain samples and in human stem cell-derived models.”
He also pointed to what sets the approach apart. “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.”
The team is now developing small molecules meant to block cysteine 148 and plans to test them in future preclinical studies. The work so far is in mice, human tissue samples and lab-grown cells, not patients. Anyone with questions about Alzheimer’s care should talk to their doctor.
