Summary: Researchers have identified a molecular “switch” that fuels chronic inflammation and synapse loss in Alzheimer’s disease. The study pinpoints a specific chemical modification—S-nitrosylation (SNO)—that abnormally activates the immune protein STING, and shows that preventing this modification protects neural connections in preclinical models.
By blocking S-nitrosylation at a single amino acid, cysteine 148, scientists were able to tamp down the brain’s damaging immune response in mouse models, preserving synapses that are otherwise lost during disease progression.
Key Facts
- STING’s role: A normal cellular early-warning system for infection, STING becomes pathologically overactive in Alzheimer’s, contributing to sustained neuroinflammation.
- S-nitrosylation (SNO): Triggered by aging, environmental toxins, and protein aggregates such as amyloid-beta, nitric oxide attaches to STING to form SNO-STING, causing the protein to cluster into inflammatory complexes.
- Precision targeting: Targeting cysteine 148 selectively prevents STING overactivation without shutting down its essential role in host defense, unlike broad-spectrum anti-inflammatory approaches.
- Synapse protection: Preventing S-nitrosylation of STING in preclinical models not only reduced inflammation but also preserved synapses—key connections required for memory and cognition.
Source: Scripps Research Institute
The brain’s innate immune system detects threats and mounts protective responses. In Alzheimer’s disease, however, these immune cells can remain chronically active, producing inflammation that harms synapses and accelerates cognitive decline.
A new preclinical study from Scripps Research identifies a redox-based molecular switch that drives this chronic neuroinflammatory state and offers a focused target for therapeutic intervention.
Published in Cell Chemical Biology on April 23, 2026, the research centers on STING (stimulator of interferon genes), a protein that normally helps cells detect cytosolic DNA and activate immune responses. The team found that in Alzheimer’s brain tissue STING is modified by S-nitrosylation—a redox change in which a nitric oxide–related group binds to a cysteine residue—producing an overactive, inflammatory form called SNO-STING.
Using mass spectrometry and redox chemical biology techniques, researchers identified cysteine 148 on STING as the critical site of S-nitrosylation. When cysteine 148 becomes S-nitrosylated, STING oligomerizes into larger complexes that trigger excessive type I interferon signaling and sustained neuroinflammation.
The modified form, SNO-STING, was detected at elevated levels in postmortem Alzheimer’s brain tissue, in human immune cells derived from induced pluripotent stem cells exposed to Alzheimer’s-related protein aggregates, and in a transgenic mouse model of the disease. Laboratory assays further showed that aggregated proteins commonly found in neurodegeneration—such as amyloid-beta and alpha-synuclein—can induce S-nitrosylation of STING, suggesting a feed-forward loop where protein aggregation and nitrosative stress amplify inflammation.
To test whether blocking this modification would be protective, the team engineered a variant of STING lacking cysteine 148 so it could not be S-nitrosylated. Introducing this modified STING into an Alzheimer’s mouse model substantially reduced microglial inflammation and, importantly, prevented synapse loss. Preservation of synapses is widely associated with protection against cognitive decline, pointing to functional benefits beyond simple reduction of inflammatory markers.
“This is a new and important therapeutic target for Alzheimer’s disease,” says senior author Stuart Lipton, Step Family Foundation Endowed Chair at Scripps Research. “By preventing STING overactivation at cysteine 148, we can quiet pathological inflammation without disabling the protein’s normal role in host defense.”
Lipton and colleagues are now pursuing small-molecule compounds designed to bind near cysteine 148 and block S-nitrosylation, with the goal of testing these candidates in further preclinical models.
The study was led by Lauren Carnevale and includes collaborators such as John Yates III, a mass spectrometry expert. Coauthors listed on the paper include 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, along with the lead investigators.
Funding: This work received support from the National Institutes of Health (including grants R35 AG071734, U01 AG088679, RF1 AG057409, R01 AG078756, R01 AG056259, R01 DA048882, DP1 DA041722 and R01 AG077046) and from the U.S. Department of Defense/U.S. Department of the Army (AR230101).
Key Questions Answered:
A: Not exactly. In Alzheimer’s, inflammation is a chronic, smoldering activation of microglia (the brain’s immune cells). Rather than resolving damage, these cells remain activated for years and can mistakenly attack and remove healthy synapses between neurons.
A: Environmental toxins can elevate nitric oxide production in the brain. This study demonstrates that increased nitric oxide can drive S-nitrosylation of STING—the “SNO-STORM”—shifting STING into a persistently activated state that sustains inflammatory signaling.
A: The findings provide a compelling lead. By identifying cysteine 148 as the precise molecular site responsible for harmful STING activation, researchers can design small molecules to block that modification. Those compounds will require further preclinical testing before any clinical trials can begin.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full to verify findings and context.
- Additional explanatory context was added by editorial staff to clarify implications for neuroinflammation and synaptic protection.
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 contributes to neuroinflammation in age-related neurological disorders, but the molecular mechanisms remain incompletely understood. Here, we show that S-nitrosylation, a redox-based posttranslational modification, regulates STING in Alzheimer’s disease. Using redox chemical biology and mass spectrometry, we identified S-nitrosylation at cysteine 148 as a critical modification that facilitates STING oligomerization and provokes excessive type I interferon signaling. This modification was observed in human Alzheimer’s postmortem brain, in human induced pluripotent stem cell–derived innate immune cells exposed to disease-related protein aggregates, and in a transgenic Alzheimer’s mouse model. Our results reveal a molecular link between nitrosative stress and dysregulated innate immunity that drives neuroinflammation and synaptic loss in Alzheimer’s disease. Targeting this redox-sensitive cysteine offers a promising strategy to modulate neuroinflammation and potentially slow disease progression.