Researchers at Scripps Research have zeroed in on a molecular switch that appears to drive the brain inflammation characteristic of Alzheimer's disease, opening a potential new avenue for treatment.
The culprit is a protein called STING, which normally acts as part of the brain's immune defense system. But in Alzheimer's patients, this protein undergoes a chemical alteration that sends it into overdrive, triggering chronic inflammation that damages the connections between nerve cells.
The chemical modification in question is called S-nitrosylation, a process where a molecule related to nitric oxide attaches to a specific spot on STING. Once this happens, the protein begins clustering into larger complexes that activate inflammatory responses. Senior researcher Stuart Lipton, who discovered S-nitrosylation over 30 years ago, described the finding as a breakthrough for understanding the disease.
The team identified the exact location where this modification occurs: a component of STING called cysteine 148. When this site gets altered, the protein becomes hyperactive. The researchers found elevated levels of this modified form, called SNO-STING, in brain tissue from deceased Alzheimer's patients, in laboratory-grown brain immune cells exposed to Alzheimer's proteins, and in mouse models of the disease.
The inflammation appears to create a vicious cycle. Protein clumps like amyloid-beta and alpha-synuclein, which accumulate in Alzheimer's brains, can trigger the S-nitrosylation of STING. This sets off inflammation that generates more nitric oxide, which then promotes further S-nitrosylation, amplifying the destructive process.
To test whether blocking this cycle could help, researchers engineered a version of STING lacking cysteine 148 and therefore unable to undergo the harmful modification. When they introduced this altered protein into mice with Alzheimer's disease, brain inflammation dropped significantly, and crucially, the synapses connecting nerve cells were protected from deterioration.
That last finding matters because preserving these connections is directly linked to preventing cognitive decline. Lipton emphasized that the approach offers a selective advantage over broader immune suppression. Blocking the STING modification leaves the protein's normal immune functions intact, still able to protect against infections.
The research team is now developing small molecules designed to specifically block cysteine 148 and plans to test them in future preclinical studies. The work was published in Cell Chemical Biology.
Author Jessica Williams: "If these molecules pan out, we're looking at a way to defuse the inflammatory bomb in Alzheimer's brains without leaving patients defenseless against infection."
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