Now, researchers at Scripps Research have identified a molecular mechanism that appears to play a key role in that process. Using human Alzheimer's brain cells and other experimental models, the team discovered a chemical change that can push the brain's immune response into overdrive. The findings, published in Cell Chemical Biology, point to a promising new target for future Alzheimer's treatments.

A Key Protein Linked to Brain Inflammation

The study focuses on a protein called STING, which normally serves as part of the body's early warning system against threats. Researchers found that in Alzheimer's disease, STING undergoes a chemical modification known as S-nitrosylation (or SNO, a reaction involving sulfur, oxygen and nitrogen). This alteration appears to make the protein excessively active, fueling harmful inflammation.

When the scientists blocked this specific chemical modification in a mouse model of Alzheimer's disease, levels of neuroinflammation dropped.

"This is a new and important therapeutic target for Alzheimer's disease," says senior author Stuart Lipton, the Step Family Foundation Endowed Chair at Scripps Research and 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, especially because we found the same pathway to be activated in human Alzheimer's brain samples and in human stem cell-derived models."

The Discovery of a Harmful Chemical Process

More than 30 years ago, Lipton discovered the biological process known as S-nitrosylation. During this reaction, a molecule related to nitric oxide (NO) attaches to a cysteine amino acid within a protein, creating what scientists call "SNO" and altering the protein's behavior.

Previous work from Lipton's laboratory has shown that this 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, the resulting disruption, described as a "SNO-STORM," can interfere with normal cellular function.

Researchers have linked this phenomenon to several diseases, including cancer, Parkinson's disease and Alzheimer's disease.

Pinpointing the Alzheimer's Switch

For the new study, Lipton's team focused on STING because earlier research had already connected it to inflammation in Alzheimer's disease.

Led by postdoctoral researcher Lauren Carnevale, the group worked with Scripps Research Professor John Yates III, a leading expert in mass spectrometry and holder of the John Lytton Young Endowed Chair. Together, they identified the exact location on STING where S-nitrosylation occurs.

Their investigation revealed that the reaction targets a specific component of the protein called cysteine 148. Once this site becomes S-nitrosylated, STING begins clustering into larger complexes that activate inflammatory responses.

The researchers detected 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.

A Self Sustaining Cycle of Inflammation

The team also discovered that protein clumps commonly associated with Alzheimer's disease, including amyloid-beta and alpha-synuclein, can trigger the S-nitrosylation of STING.

This finding 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.

To test whether interrupting this cycle could help, the researchers engineered a version of STING that lacked cysteine 148 and therefore could not undergo S-nitrosylation.

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. Preserving these connections is strongly associated with protection against the cognitive decline seen in dementia.

A Potential New Treatment Strategy

"What makes this target particularly promising is that we can quiet the pathological overactivation of STING without shutting down the normal immune response," says Lipton. "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 research team is now developing small molecules designed to block cysteine 148 and plans to evaluate them in future preclinical studies.

In addition to Lipton, Carnevale and Yates, authors of the study, "Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer's disease brain," are Piu Banerjee, Xu Zhang, Jazmin Navarro, Charlene K Raspur, Parth Patel, Tomohiro Nakamura, Emily Schahrer, Henry Scott, Nhi Lang, Jolene K. Diedrich and Amanda J. Roberts of Scripps Research.

This work was supported in part by the National Institutes of Health (R35 AG071734, U01 AG088679, RF1 AG057409, R01 AG078756, R01 AG056259, R01 DA048882, DP1 DA041722 and R01 AG077046), and the U.S. Department of Defense/U.S. Department of the Army (AR230101).