Scientists have identified a molecular switch that appears to drive damaging brain inflammation in Alzheimer's disease. This discovery could lead to new treatment targets. Researchers at Scripps Research found that a protein called STING becomes chemically altered. This alteration causes the brain's immune system to remain in an overactive state. This chronic activation harms the connections between nerve cells.
The study focused on the protein STING, which is typically part of the body's early warning system. In Alzheimer's disease, STING undergoes a chemical modification called S-nitrosylation. This modification involves a reaction with sulfur, oxygen, and nitrogen. This change makes the protein excessively active, promoting harmful inflammation. When scientists blocked this specific modification in a mouse model of Alzheimer's, neuroinflammation levels decreased.
Stuart Lipton, a senior author and clinical neurologist at Scripps Research, stated that this is a new and important therapeutic target. Blocking this switch in mice reduced inflammation and protected nerve cell connections. The same pathway was active in human Alzheimer's brain samples and human stem cell models. The S-nitrosylation process can be triggered by factors like aging, inflammation, and environmental exposures.
Researchers found that protein clumps associated with Alzheimer's, such as amyloid-beta, can trigger STING's S-nitrosylation. This suggests a self-sustaining cycle of inflammation. Protein aggregates, along with aging and environmental factors, may initiate inflammation. This inflammation generates nitric oxide, which promotes STING S-nitrosylation, further amplifying the inflammatory process. The team engineered a version of STING that could not undergo S-nitrosylation. Introducing this modified protein into a mouse model resulted in lower inflammation and protected nerve cell synapses.
This approach aims to quiet the pathological overactivation of STING without shutting down the normal immune response. STING is still needed to protect against infections. Targeting cysteine 148 prevents STING from becoming overactivated, rather than blocking the entire molecule. The research team is now developing small molecules to block cysteine 148 for future preclinical studies.
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