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Blocking this molecular switch reduces inflammation and protects the very brain cell connections lost in Alzheimer\u2019s. Credit Neuroscience News<\/p>\nSummary: Researchers discovered a molecular \u201cswitch\u201d that drives chronic inflammation and synapse loss in Alzheimer\u2019s disease. The study identifies a chemical modification called S-nitrosylation (SNO) that overactivates a key immune protein named STING.<\/p>\n
By blocking this specific modification at a single building block, cysteine 148, scientists were able to quiet the brain\u2019s \u201cimmune storm\u201d in mouse models, protecting the vital nerve cell connections that are typically destroyed by the disease.<\/p>\n
Key FactsThe STING Protein: Normally an \u201cearly-warning system\u201d for infections, STING becomes pathologically overactive in Alzheimer\u2019s 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 \u201cSNO-STING.\u201d 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\u2019s, leaving the body\u2019s ability to fight infections intact.Synapse Protection: In preclinical models, preventing S-nitrosylation of STING didn\u2019t just reduce inflammation, it actively stopped the degradation of synapses, the connections required for memory and learning.<\/p>\n
Source: Scripps Research Institute<\/p>\n
The brain has its own immune system, which detects threats and mounts a defense. A growing body of evidence has shown that in Alzheimer\u2019s disease, those immune cells are chronically overactivated, causing inflammation that damages the connections between brain cells.<\/p>\n
Now, in a preclinical study using human Alzheimer\u2019s brain cells, scientists at Scripps Research have identified a molecular switch\u2014and potential drug target\u2014responsible for driving that chronic inflammation.\u00a0<\/p>\n
Blocking this molecular switch reduces inflammation and protects the very brain cell connections lost in Alzheimer\u2019s. Credit Neuroscience News<\/p>\n
The research, published in\u00a0Cell Chemical Biology\u00a0on April 23, 2026, centers on a protein called STING, which normally functions as part of the immune system\u2019s early-warning system.<\/p>\n
In the brains of people with Alzheimer\u2019s, 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.<\/p>\n
\u201cThis is a new and important therapeutic target for Alzheimer\u2019s disease,\u201d says senior author\u00a0Stuart Lipton, the Step Family Foundation Endowed Chair at Scripps Research and a clinical neurologist.<\/p>\n
\u201cIt\u2019s exciting to see that blocking this switch in mice reduces inflammation and protects the very brain cell connections that are lost in Alzheimer\u2019s, especially because we found the same pathway to be activated in human Alzheimer\u2019s brain samples and in human stem cell-derived models.\u201d<\/p>\n
Over three decades ago, Lipton, who\u2019s 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 \u201cSNO\u201d and thus regulates the protein\u2019s function. His lab has shown that SNO\u2014which can be triggered by aging, neuroinflammation and environmental toxins such as air pollution and wildfire smoke\u2014disrupts a variety of different proteins in the body.<\/p>\n
The modification, causing a veritable \u201cSNO-STORM\u201d to disrupt protein function, has been linked to several human conditions, including\u00a0cancer,\u00a0Parkinson\u2019s disease\u00a0and\u00a0Alzheimer\u2019s.<\/p>\n
In this new study, the team focused on the protein STING, which was previously linked to Alzheimer\u2019s inflammation. Lipton\u2019s group, led by postdoctoral researcher Lauren Carnevale, collaborated with Professor\u00a0John Yates III, a leading mass spectrometry expert at Scripps Research and holder of the John Lytton Young Endowed Chair.<\/p>\n
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.<\/p>\n
The team found high levels of the chemically modified form of STING (called SNO-STING) in postmortem brain tissue from Alzheimer\u2019s patients, in human brain immune cells grown in the lab and exposed to Alzheimer\u2019s proteins, and in a mouse model of the disease.<\/p>\n
In laboratory experiments, the team showed that the clumps of proteins found in the brain in Alzheimer\u2019s\u2014including amyloid-beta and alpha-synuclein\u2014can themselves trigger the S-nitrosylation reaction in STING.<\/p>\n
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.<\/p>\n
The researchers then engineered a version of STING lacking cysteine 148 so it couldn\u2019t be S-nitrosylated. When this modified protein was introduced into a mouse model of Alzheimer\u2019s, 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.<\/p>\n
\u201cWhat makes this target particularly promising is that we can quiet the pathological overactivation of STING without shutting down the normal immune response,\u201d says Lipton.<\/p>\n
\u201cYou still need STING to protect yourself from infections, and when we target cysteine 148, we\u2019re not blocking the entire molecule; we\u2019re just preventing STING from becoming overactivated.\u201d<\/p>\n
Lipton\u2019s group is now working to develop small molecules that block cysteine 148 for testing in preclinical models.<\/p>\n
In addition to Lipton, Carnevale and Yates, authors of the study, \u201cRedox regulation of neuroinflammatory pathways contributes to damage in Alzheimer\u2019s disease brain,\u201d 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.<\/p>\n
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).<\/p>\n
Key Questions Answered:Q: Is \u201cbrain inflammation\u201d the same as the swelling you get from an injury?<\/p>\n
A: Not quite. In Alzheimer\u2019s, it\u2019s a \u201csmoldering\u201d chronic activation of the brain\u2019s immune cells (microglia). Instead of healing the brain, these cells stay \u201con\u201d for years, eventually attacking and eating the healthy connections (synapses) between neurons.<\/p>\n
Q: How do environmental factors like wildfire smoke trigger Alzheimer\u2019s?<\/p>\n
A: Environmental toxins increase the production of nitric oxide in the brain. This study shows that nitric oxide triggers the S-nitrosylation process, the \u201cSNO-STORM\u201d, which flips the STING switch into a permanent \u201con\u201d position, driving the inflammation cycle.<\/p>\n
Q: Does this mean a pill for Alzheimer\u2019s inflammation is on the horizon?<\/p>\n
A: It\u2019s a very strong lead. Because the researchers identified the exact spot (cysteine 148) where the damage starts, they are now developing \u201csmall molecule\u201d drugs designed to sit on that spot and prevent the \u201cSNO\u201d modification from happening.<\/p>\n
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\u2019s disease and neurology research news<\/p>\n
Author:\u00a0Press Office<\/a>
Source:\u00a0Scripps Research<\/a>
Contact:\u00a0Press Office \u2013 Scripps Research
Image:\u00a0The image is credited to Neuroscience News<\/p>\n