New Research Identifies Potential Target to Reduce Brain Inflammation in Alzheimer’s Disease
Scientists have identified a promising new therapeutic target that could help reduce the harmful brain inflammation associated with Alzheimer’s disease, according to new research from the United States.
Researchers at the Scripps Research have discovered a molecular mechanism that appears to drive chronic inflammation in the brains of people living with Alzheimer’s disease. Their findings, published in the journal Cell Chemical Biology on 23 April 2026, may open the door to the development of new treatments aimed at slowing disease progression.
Alzheimer’s disease is increasingly recognised not only as a disorder characterised by the accumulation of abnormal proteins in the brain, but also as a condition involving significant immune system dysfunction. The brain possesses its own immune defence system, designed to identify and respond to threats. However, growing evidence suggests that in Alzheimer’s disease these immune cells become chronically overactive, triggering persistent inflammation that damages the connections between nerve cells.
The latest study focuses on a protein known as STING, which normally acts as part of the body’s immune early-warning system. The research team found that in Alzheimer’s disease, STING undergoes a chemical modification called S-nitrosylation, a process involving nitric oxide-related molecules that alters the protein’s behaviour and promotes excessive immune activation.
Senior author Stuart Lipton, a clinical neurologist and holder of the Step Family Foundation Endowed Chair at Scripps Research, described the discovery as a significant advance in understanding the disease.
“This is a new and important therapeutic target for Alzheimer’s disease,” he said. “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.”
The research builds on more than three decades of work by Lipton and colleagues investigating S-nitrosylation, a process first identified by his laboratory. Previous studies have linked excessive S-nitrosylation to a range of conditions, including cancer, Parkinson’s disease and Alzheimer’s disease. The process can be triggered by ageing, inflammation and environmental factors such as air pollution and wildfire smoke.
In the current study, researchers worked with human Alzheimer’s brain cells, post-mortem brain tissue and laboratory mouse models. The team, led by postdoctoral researcher Lauren Carnevale and collaborating with mass spectrometry specialist John Yates III, identified a specific site on the STING protein known as cysteine 148.
They found that when this site becomes chemically modified through S-nitrosylation, STING proteins cluster together and trigger inflammatory responses. Elevated levels of the modified form, known as SNO-STING, were detected in Alzheimer’s patient brain tissue, human brain immune cells exposed to Alzheimer’s-related proteins, and animal models of the disease.
The researchers also discovered that protein aggregates commonly associated with neurodegenerative disease, including amyloid-beta and alpha-synuclein, can directly trigger the S-nitrosylation process. This suggests a potentially self-perpetuating cycle in which protein build-up, ageing and environmental influences generate inflammation, which then promotes further activation of STING and additional inflammation.
To investigate whether interrupting this process could be beneficial, the team engineered a version of STING that lacked the cysteine 148 site and could not undergo S-nitrosylation. When introduced into a mouse model of Alzheimer’s disease, the modified protein significantly reduced inflammation in brain immune cells and protected synapses – the vital connections between nerve cells that are progressively lost during dementia.
Preserving synapses is widely regarded as one of the key indicators of protection against cognitive decline.
Importantly, the researchers believe the approach may offer a way to dampen harmful inflammation without compromising the body’s normal immune defences.
“What makes this target particularly promising is that we can quiet the pathological overactivation of STING without shutting down the normal immune response,” Lipton explained. “You still need STING to protect yourself from infections. By targeting cysteine 148, we’re not blocking the entire molecule; we’re simply preventing it from becoming overactivated.”
The Scripps Research team is now developing small-molecule compounds designed to block the cysteine 148 site and plans to test these potential treatments in further preclinical studies.
While the research remains at an early stage, the findings offer fresh hope that targeting brain inflammation could become an important strategy in the future treatment of Alzheimer’s disease, a condition that affects hundreds of thousands of people across the UK and places a significant burden on care services, families and communities.
