Summary: Researchers have identified a molecular “switch” that drives chronic inflammation and synapse loss in Alzheimer’s disease. The study pinpoints a chemical modification called S-nitrosylation (SNO) that overactivates the immune protein STING, and shows that preventing this change protects neuronal connections in preclinical models.
By stopping S-nitrosylation at a single amino acid—cysteine 148—scientists were able to calm the brain’s excessive immune response in mice and preserve the synapses essential for memory and learning.
Key Facts
- STING’s role: STING normally acts as an early-warning sensor in innate immunity. In Alzheimer’s-affected brains it becomes pathologically overactive, fueling chronic neuroinflammation.
- S-nitrosylation (SNO): Triggered by aging, environmental toxins and aggregated proteins (for example, amyloid-beta), nitric oxide adds an SNO group to STING. This SNO-STING form drives the protein to cluster into inflammatory complexes.
- Targeted approach: Rather than suppressing immune function broadly, blocking SNO at cysteine 148 prevents STING overactivation while preserving normal immune responses to infections.
- Synapse protection: In laboratory and animal experiments, preventing STING S-nitrosylation reduced inflammation and preserved synapses—connections between neurons that underlie cognition.
Source: Scripps Research
The brain maintains its own immune surveillance system. Growing evidence indicates that in Alzheimer’s disease this system becomes chronically activated, producing inflammation that harms neuronal connections. In a new preclinical study using human Alzheimer’s brain cells and animal models, researchers at Scripps Research have uncovered a molecular switch that underlies this harmful, long-lasting immune activation.
Published in Cell Chemical Biology on April 23, 2026, the study focuses on STING, a protein that normally helps detect threats and trigger immune responses. The investigators found that in the brains of people with Alzheimer’s, STING is modified by S-nitrosylation—a chemical attachment involving nitric oxide—that drives the protein into a hyperactive, inflammatory state. Blocking that modification in a mouse model reduced neuroinflammation and preserved synaptic integrity.
Senior author Stuart Lipton, Step Family Foundation Endowed Chair at Scripps Research and a clinical neurologist, calls the finding a promising new therapeutic target. The same pathway was observed in human Alzheimer’s brain tissue and in human stem cell-derived immune cells, strengthening the link between the molecular mechanism and disease pathology.
Lipton’s laboratory originally characterized S-nitrosylation decades ago: a nitric oxide–related molecule binds to a cysteine residue in a protein, forming an SNO group that alters the protein’s function. His team has shown SNO formation can be triggered by aging, chronic neuroinflammation and environmental exposures such as air pollution and wildfire smoke. SNO-related disruptions have been implicated in conditions ranging from cancer to Parkinson’s and Alzheimer’s disease.
In this study, the researchers zeroed in on STING and detected S-nitrosylation specifically at cysteine 148. When this residue carries an SNO group, STING aggregates into larger oligomers that initiate excessive type I interferon signaling and sustain inflammation. The chemically modified form, SNO-STING, was abundant in postmortem Alzheimer’s brain tissue, in cultured human brain immune cells exposed to Alzheimer’s-related protein aggregates, and in a transgenic mouse model of the disease.
Laboratory experiments demonstrated that protein aggregates commonly associated with neurodegeneration—such as amyloid-beta and alpha-synuclein—can themselves trigger S-nitrosylation of STING. This suggests a feed-forward cycle in which protein aggregation, environmental factors and aging increase nitric oxide production, which in turn drives SNO-STING formation and ongoing inflammation.
To test causality, the team engineered a form of STING that lacks cysteine 148 and therefore cannot be S-nitrosylated. Delivering this modified STING into an Alzheimer’s mouse model substantially reduced inflammatory markers in brain immune cells and, importantly, preserved synapses that are normally lost in the disease. Preservation of synaptic connections is closely tied to maintaining cognitive function.
Unlike broad anti-inflammatory strategies that risk impairing host defense, targeting the redox-sensitive cysteine appears to selectively prevent pathological overactivation without disabling STING’s protective roles. Lipton emphasizes that blocking cysteine 148 does not eliminate STING activity entirely; it prevents the harmful, sustained “on” state associated with disease.
The research team is now working to develop small molecules that bind cysteine 148 and block S-nitrosylation for further preclinical testing. The study’s authors include 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.
Funding: This research was supported in part by the National Institutes of Health and the U.S. Department of Defense/U.S. Department of the Army.
Key Questions Answered:
A: Not exactly. In Alzheimer’s, inflammation reflects a chronic, low-grade activation of microglia (the brain’s immune cells). Instead of resolving an injury, these cells remain activated for years and can attack healthy synapses, contributing to cognitive decline.
A: Environmental toxins can elevate nitric oxide production in the brain. This study shows nitric oxide can drive S-nitrosylation, creating SNO-STING and sustaining an inflammatory cycle that may accelerate neurodegenerative processes.
A: The findings represent a strong lead. By identifying cysteine 148 as the critical site for harmful modification, researchers can develop small molecules designed to prevent SNO attachment at that position. Those compounds will require further preclinical development before any clinical testing.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by the editorial team.
- Additional context was added by staff for clarity.
About this Alzheimer’s disease and neurology research news
Author: Press Office
Source: Scripps Research
Contact: Press Office – Scripps Research
Image: Image 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 et al., published in 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 mechanisms behind this activation have been unclear. This study identifies protein S-nitrosylation, a redox-dependent posttranslational modification, as a regulator of the stimulator of interferon genes (STING) protein in Alzheimer’s disease.
Using redox chemical biology and mass spectrometry, the authors identified S-nitrosylation at cysteine 148 as a key modification that promotes STING oligomerization and triggers excessive type I interferon signaling. This modification was detected in human Alzheimer’s postmortem brain tissue, in human induced pluripotent stem cell–derived innate immune cells exposed to disease-related protein aggregates, and in a transgenic Alzheimer’s mouse model.
The findings reveal a molecular connection 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.