Alzheimer’s disease is the most common cause of dementia, affecting millions of people around the world. It slowly destroys memory, thinking skills, and the ability to carry out everyday activities.
Despite decades of research, scientists are still trying to understand exactly why the disease develops and how it progresses over time.
One area receiving increasing attention is the brain’s immune system. Just as the rest of the body has immune defenses that fight infections and repair damage, the brain has its own specialized immune cells. Under normal conditions, these cells help protect nerve cells and keep the brain healthy.
However, researchers have found that in Alzheimer’s disease, these protective cells can become trapped in a state of constant activation. Instead of helping the brain, they begin producing ongoing inflammation that may contribute to damage and cognitive decline.
Now, scientists at Scripps Research have identified an important molecular process that appears to fuel this harmful inflammation. Their findings were published in the journal Cell Chemical Biology and may open the door to new treatments designed to slow or prevent the progression of Alzheimer’s disease.
The study focused on a protein called STING. This protein normally acts as part of the body’s early warning system. When threats such as infections or cellular damage are detected, STING helps activate immune responses that protect tissues. In healthy situations, this response is carefully controlled and temporary.
The researchers discovered that in Alzheimer’s disease, STING undergoes a chemical change called S-nitrosylation. This process occurs when a molecule related to nitric oxide attaches to a specific part of the protein. Once this happens, STING becomes excessively active and begins driving inflammation far beyond normal levels.
The work builds on decades of research by Dr. Stuart Lipton, a neurologist and senior author of the study. More than thirty years ago, Lipton helped discover the biological process known as S-nitrosylation. Scientists have since found that this process can alter the behavior of many proteins throughout the body.
Previous research has shown that aging, chronic inflammation, air pollution, wildfire smoke, and other environmental factors can increase this chemical modification. When large numbers of proteins are affected, the resulting disruption can interfere with normal cellular functions and contribute to disease.
To investigate Alzheimer’s disease, the researchers studied human brain tissue, laboratory-grown human brain cells, and mouse models of the disease. They identified a specific location on the STING protein called cysteine 148. This turned out to be the critical site where S-nitrosylation occurs.
Once modified, STING molecules began clustering together and triggering inflammatory signals. The team found high levels of this altered form of STING in brain samples from people with Alzheimer’s disease. Similar findings appeared in human brain immune cells exposed to Alzheimer’s-related proteins and in mice with the disease.
The researchers also discovered that protein clumps commonly linked to Alzheimer’s disease, including amyloid-beta and alpha-synuclein, can trigger this chemical change.
This suggests a vicious cycle may develop. Protein clumps stimulate inflammation, inflammation increases nitric oxide production, nitric oxide modifies STING, and overactive STING drives even more inflammation.
To see whether interrupting this cycle could help, the team engineered a version of STING that could not undergo the chemical modification. When introduced into mice with Alzheimer’s disease, inflammation in the brain dropped significantly. Even more importantly, the tiny connections between nerve cells, known as synapses, were protected.
Synapses are essential for learning, memory, and communication between brain cells. Loss of synapses is strongly associated with cognitive decline and dementia. Protecting them is considered one of the most important goals in Alzheimer’s research.
The scientists believe their findings are particularly promising because blocking this specific modification does not completely shut down STING. The protein can still perform its normal role in protecting against infections. Instead, the approach targets only the harmful overactivation linked to disease.
This study provides strong evidence that excessive activation of STING contributes to brain inflammation in Alzheimer’s disease.
The findings are strengthened by the use of multiple experimental systems, including human brain tissue, stem-cell-derived human cells, and animal models. The discovery of a specific target, cysteine 148, offers a clear direction for drug development.
However, the work remains at the preclinical stage. It is not yet known whether blocking this pathway will be safe or effective in humans. Nevertheless, the study identifies one of the most promising new inflammation-related targets in Alzheimer’s research and could help guide the development of future treatments.
If you care about Alzheimer’s disease, please read studies about the protective power of dietary antioxidants against Alzheimer’s, and eating habits linked to higher Alzheimer’s risk.
For more health information, please see recent studies that oral cannabis extract may help reduce Alzheimer’s symptoms, and Vitamin E may help prevent Parkinson’s disease.
Source: Scripps Research.
