The immune cells of the Alzheimer’s brain are stuck in the “on” position. That has been suspected for some time. What scientists at Scripps Research now say they have is a candidate for the switch itself.
Their preclinical study appeared in Cell Chemical Biology on April 23, 2026. It centers on STING, a protein that normally acts as part of the immune system’s early-warning network. In the brains of people with Alzheimer’s, the team found that STING undergoes a chemical modification called S-nitrosylation, or SNO, a reaction involving sulfur, oxygen and nitrogen. That change pushes the protein into overactivity. When the researchers blocked it in a mouse model of the disease, neuroinflammation fell.
Pinning down the spot
Senior author Stuart Lipton, a clinical neurologist who holds the Step Family Foundation Endowed Chair at Scripps Research, first described S-nitrosylation more than three decades ago. In the process, a molecule related to nitric oxide attaches to a cysteine amino acid in a protein and changes how it behaves. His lab has shown that aging, neuroinflammation and environmental toxins such as air pollution and wildfire smoke can trigger it.
For this work, postdoctoral researcher Lauren Carnevale led the effort with John Yates III, a mass spectrometry specialist at the institute. Together they located the modification on a single building block of STING, cysteine 148. When that site is S-nitrosylated, STING clusters into larger complexes and sets off inflammation.
The modified protein, called SNO-STING, turned up at high levels in postmortem brain tissue from Alzheimer’s patients, in human brain immune cells grown in the lab and exposed to Alzheimer’s proteins, and in the mouse model.
A possible loop
In laboratory experiments, the protein clumps that mark Alzheimer’s, including amyloid-beta and alpha-synuclein, could themselves trigger the reaction. That hints at a cycle, the team says: clumps, aging and environmental influences produce inflammation, inflammation generates nitric oxide, nitric oxide modifies STING, and modified STING drives still more inflammation.
To test the idea, the researchers engineered a STING that lacks cysteine 148 and cannot be modified. Placed into the Alzheimer’s mouse model, it left brain immune cells noticeably less inflamed, and the synapses between nerve cells were protected from breaking down. Loss of synapses is known to track with the cognitive decline of dementia.
“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,” Lipton said, noting the same pathway was active in human Alzheimer’s brain samples and in human stem cell-derived models.
He also stressed a design point. “You still need STING to protect yourself from infections,” he said, and aiming at cysteine 148 prevents overactivation without blocking the whole molecule.
This is early science. Lipton’s group is now working on small molecules that block cysteine 148, for testing in preclinical models, and nothing here has reached patients. Anyone worried about memory or Alzheimer’s should talk to their doctor.
Sources
- How a chemical reaction triggers brain inflammation in Alzheimer's disease – Scripps Research
- Scientists Discover “Molecular Switch” That Fuels Alzheimer’s Brain Inflammation
