Scientists at Scripps Research have identified a molecular "switch" that appears to fuel the damaging brain inflammation seen in Alzheimer's disease, offering a promising new target for future treatments. The protein STING becomes chemically altered in a way that keeps the brain's immune system stuck in overdrive, harming the connections between nerve cells. When researchers blocked this specific alteration in a mouse model of Alzheimer's disease, brain inflammation dropped significantly and synapses were protected from deterioration.

What Is STING and Why Does It Matter in Alzheimer's?

STING is a protein that normally serves as part of the body's early warning system against threats. In Alzheimer's disease, STING undergoes a chemical modification called S-nitrosylation, a reaction involving sulfur, oxygen, and nitrogen. This alteration makes the protein excessively active, fueling harmful inflammation that damages the connections between brain cells.

The research team discovered high levels of this altered form, known as SNO-STING, in postmortem brain tissue from people with Alzheimer's disease. Elevated levels were also found in human brain immune cells grown in the laboratory and exposed to Alzheimer's-related proteins, as well as in a mouse model of the disease.

How Does This Inflammation Switch Get Turned On?

Researchers found that protein clumps commonly associated with Alzheimer's disease, including amyloid-beta and alpha-synuclein, can trigger the S-nitrosylation of STING. This discovery suggests that inflammation may become trapped in a repeating cycle. Protein aggregates, together with aging and environmental factors, may spark inflammation that generates nitric oxide. That nitric oxide can then promote S-nitrosylation of STING, which drives even more inflammation and further amplifies the process.

The research also revealed that this harmful chemical process can be triggered by factors such as aging, inflammation, and environmental exposures including air pollution and wildfire smoke. When large numbers of proteins are affected by this process, the resulting disruption can interfere with normal cellular function.

What Happens When Scientists Block This Switch?

To test whether interrupting this cycle could help, researchers engineered a version of STING that lacked cysteine 148, the specific location where S-nitrosylation occurs. When this modified protein was introduced into a mouse model of Alzheimer's disease, brain immune cells showed much lower levels of inflammation. Just as importantly, the synapses that connect nerve cells were protected from deterioration.

"What makes this target particularly promising is that we can quiet the pathological overactivation of STING without shutting down the normal immune response," said Stuart Lipton, the Step Family Foundation Endowed Chair at Scripps Research and a clinical neurologist.

Stuart Lipton, Step Family Foundation Endowed Chair and Clinical Neurologist at Scripps Research

Preserving these connections is strongly associated with protection against the cognitive decline seen in dementia. This finding is significant because it suggests a way to reduce harmful inflammation while maintaining the brain's ability to protect itself from infections.

Steps Toward a New Alzheimer's Treatment Strategy

• Identifying the Target: Researchers pinpointed cysteine 148 as the exact location on STING where the harmful chemical modification occurs, making it a specific and potentially precise therapeutic target.
• Testing in Models: The team confirmed that blocking this modification reduces inflammation and protects nerve cell connections in both mouse models and human brain cells grown in the laboratory.
• Developing Small Molecules: The research team is now developing small molecules designed to block cysteine 148 and plans to evaluate them in future preclinical studies.

The study, published in Cell Chemical Biology, represents a significant advance in understanding how Alzheimer's disease damages the brain. By focusing on this specific chemical modification rather than trying to block the entire STING protein, researchers believe they can reduce harmful inflammation without compromising the immune system's ability to fight infections.

"This is a new and important therapeutic target for Alzheimer's disease. 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," explained Stuart Lipton.

Stuart Lipton, Step Family Foundation Endowed Chair and Clinical Neurologist at Scripps Research

The research was led by postdoctoral researcher Lauren Carnevale and conducted in collaboration with John Yates III, a leading expert in mass spectrometry at Scripps Research. The work was supported by the National Institutes of Health and the U.S. Department of Defense.

While these findings are promising, the research is still in early stages. The next step involves developing and testing small molecules that can safely block the harmful chemical modification of STING in living organisms. If successful in future preclinical studies, this approach could eventually lead to new medications that slow or prevent the cognitive decline associated with Alzheimer's disease.