Summary: Researchers discovered a molecular “switch” that drives chronic inflammation and synapse loss in Alzheimer’s disease. The study identifies a chemical modification called S-nitrosylation (SNO) that overactivates a key immune protein named STING.
By blocking this specific modification at a single building block, cysteine 148, scientists were able to quiet the brain’s “immune storm” in mouse models, protecting the vital nerve cell connections that are typically destroyed by the disease.
Key Facts
- The STING Protein: Normally an “early-warning system” for infections, STING becomes pathologically overactive in Alzheimer’s brains, leading to chronic neuroinflammation.
- The SNO Modification: Triggered by aging, toxins, and protein clumps (like amyloid-beta), nitric oxide binds to STING to create “SNO-STING.” This causes the protein to cluster into inflammatory complexes.
- Precision Targeting: Unlike many anti-inflammatory drugs that shut down the entire immune system, targeting cysteine 148 only blocks the overactivation caused by Alzheimer’s, leaving the body’s ability to fight infections intact.
- Synapse Protection: In preclinical models, preventing S-nitrosylation of STING didn’t just reduce inflammation, it actively stopped the degradation of synapses, the connections required for memory and learning.
Source: Scripps Research Institute
The brain has its own immune system, which detects threats and mounts a defense. A growing body of evidence has shown that in Alzheimer’s disease, those immune cells are chronically overactivated, causing inflammation that damages the connections between brain cells.
Now, in a preclinical study using human Alzheimer’s brain cells, scientists at Scripps Research have identified a molecular switch—and potential drug target—responsible for driving that chronic inflammation.
The research, published in Cell Chemical Biology on April 23, 2026, centers on a protein called STING, which normally functions as part of the immune system’s early-warning system.
In the brains of people with Alzheimer’s, the team discovered that STING undergoes a chemical modification known as S-nitrosylation (or SNO, a reaction involving sulfur, oxygen and nitrogen) that promotes its overactivation. Blocking this chemical change to STING in a mouse model of the disease decreased neuroinflammation.
“This is a new and important therapeutic target for Alzheimer’s disease,” says senior author Stuart Lipton, the Step Family Foundation Endowed Chair at Scripps Research and a clinical neurologist.
“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, especially because we found the same pathway to be activated in human Alzheimer’s brain samples and in human stem cell-derived models.”
Over three decades ago, Lipton, who’s also the founding co-director of the Neurodegeneration New Medicines Center at Scripps Research, discovered the S-nitrosylation process, in which a molecule related to nitric oxide (NO) binds to a cysteine amino acid in proteins, producing “SNO” and thus regulates the protein’s function. His lab has shown that SNO—which can be triggered by aging, neuroinflammation and environmental toxins such as air pollution and wildfire smoke—disrupts a variety of different proteins in the body.
The modification, causing a veritable “SNO-STORM” to disrupt protein function, has been linked to several human conditions, including cancer, Parkinson’s disease and Alzheimer’s.
In this new study, the team focused on the protein STING, which was previously linked to Alzheimer’s inflammation. Lipton’s group, led by postdoctoral researcher Lauren Carnevale, collaborated with Professor John Yates III, a leading mass spectrometry expert at Scripps Research and holder of the John Lytton Young Endowed Chair.
They pinpointed exactly where on STING an S-nitrosylation reaction occurred, homing in on one specific building block of the protein: cysteine 148. When cysteine 148 is S-nitrosylated, they discovered, STING clusters into larger complexes and triggers inflammation.
The team found high levels of the chemically modified form of STING (called SNO-STING) 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 a mouse model of the disease.
In laboratory experiments, the team showed that the clumps of proteins found in the brain in Alzheimer’s—including amyloid-beta and alpha-synuclein—can themselves trigger the S-nitrosylation reaction in STING.
This finding suggests that inflammation occurs in a cycle: initial protein clumps, coupled with environmental influences and aging, could cause inflammation that generates NO, driving S-nitrosylation of STING, which in turn drives more inflammation.
The researchers then engineered a version of STING lacking cysteine 148 so it couldn’t be S-nitrosylated. When this modified protein was introduced into a mouse model of Alzheimer’s, brain immune cells showed significantly less inflammation, and critically, the connections between nerve cells (called synapses) were protected from degradation. This preservation of synapses is known to correlate with protection from the cognitive decline of dementia.
“What makes this target particularly promising is that we can quiet the pathological overactivation of STING without shutting down the normal immune response,” says Lipton.
“You still need STING to protect yourself from infections, and when we target cysteine 148, we’re not blocking the entire molecule; we’re just preventing STING from becoming overactivated.”
Lipton’s group is now working to develop small molecules that block cysteine 148 for testing in preclinical models.
In addition to Lipton, Carnevale and Yates, authors of the study, “Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer’s disease brain,” are Piu Banerjee, Xu Zhang, Jazmin Navarro, Charlene K Raspur, Parth Patel, Tomohiro Nakamura, Emily Schahrer, Henry Scott, Nhi Lang, Jolene K. Diedrich and Amanda J. Roberts of Scripps Research.
Funding: This work was supported in part by the National Institutes of Health (R35 AG071734, U01 AG088679, RF1 AG057409, R01 AG078756, R01 AG056259, R01 DA048882, DP1 DA041722 and R01 AG077046), and the U.S. Department of Defense/U.S. Department of the Army (AR230101).
Key Questions Answered:
A: Not quite. In Alzheimer’s, it’s a “smoldering” chronic activation of the brain’s immune cells (microglia). Instead of healing the brain, these cells stay “on” for years, eventually attacking and eating the healthy connections (synapses) between neurons.
A: Environmental toxins increase the production of nitric oxide in the brain. This study shows that nitric oxide triggers the S-nitrosylation process, the “SNO-STORM”, which flips the STING switch into a permanent “on” position, driving the inflammation cycle.
A: It’s a very strong lead. Because the researchers identified the exact spot (cysteine 148) where the damage starts, they are now developing “small molecule” drugs designed to sit on that spot and prevent the “SNO” modification from happening.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease and neurology research news
Author: Press Office
Source: Scripps Research
Contact: Press Office – Scripps Research
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer’s disease brain” by Lauren N. Carnevale, Piu Banerjee, Xu Zhang, Jazmin Navarro, Charlene K. Raspur, Parth Patel, Tomohiro Nakamura, Emily Schahrer, Henry Scott, Nhi Lang, Jolene K. Diedrich, Amanda J. Roberts, John R. Yates III, and Stuart A. Lipton. Cell Chemical Biology
DOI:10.1016/j.chembiol.2026.03.017
Abstract
Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer’s disease brain
Aberrant activation of innate immune signaling is known to contribute to neuroinflammation in age-related neurological disorders, but the mechanisms underlying this activation remain unclear.
Here, we discovered that protein S-nitrosylation, a redox-based posttranslational modification, regulates the stimulator of interferon genes (STING) protein in Alzheimer’s disease (AD).
Using a combination of redox chemical biology and mass spectrometry, we identified S-nitrosylation at cysteine 148 as a critical modification facilitating STING oligomerization and triggering excessive type I interferon signaling in a causal fashion.
This modification was observed in human AD postmortem brain tissue, in human induced pluripotent stem cell (hiPSC)-derived innate immune cells exposed to AD-related protein aggregates, and in a transgenic AD mouse model.
Our findings reveal a novel molecular link between nitrosative stress and dysregulated innate immunity that drives neuroinflammation and synaptic loss in AD.
Targeting this redox-sensitive cysteine presents a promising therapeutic strategy to modulate neuroinflammation and potentially slow disease progression.
