Study Overview
A groundbreaking preclinical study led by Scripps Research, published in Cell Chemical Biology on April 23, 2026, has identified a critical molecular switch in the brain's immune cells that drives chronic inflammation in Alzheimer's disease.
The research focuses on the STING protein, which normally functions as part of the immune system's early-warning system. In Alzheimer's, STING undergoes a chemical modification called S-nitrosylation (SNO), which promotes overactivation and harmful inflammation.
"Targeting cysteine 148 may allow modulation of pathological STING overactivation without completely shutting down normal immune responses."
Key Findings
- The researchers pinpointed that S-nitrosylation occurs at a specific amino acid, cysteine 148, on the STING protein.
- High levels of SNO-STING were found in postmortem brain tissue from Alzheimer's patients, in lab-grown human brain immune cells exposed to Alzheimer's proteins, and in a mouse model of the disease.
- Protein clumps associated with Alzheimer's, including amyloid-beta and alpha-synuclein, can trigger S-nitrosylation of STING.
- Blocking S-nitrosylation of STING in a mouse model reduced neuroinflammation and protected synaptic connections between nerve cells.
Implications
The team is actively developing small molecules designed to block cysteine 148. This approach could allow researchers to modulate pathological STING overactivation in Alzheimer's disease without completely shutting down normal, beneficial immune responses.
Study Authors and Funding
The study, titled "Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer's disease brain," was authored by Lauren Carnevale, Stuart Lipton, John Yates III, and others at Scripps Research. Funding was provided by the National Institutes of Health and the U.S. Department of Defense.