Air pollution contributes to almost 7 million premature deaths every year, and its effects go far beyond the lungs. Breathing in the smoke of forest fires or the Smog of the city related to the car not only increases the risk of asthma and heart disease, but can also contribute to brain conditions as diverse as Alzheimer’s and autism.
Scripps Research scientists have discovered how a chemical change in the brain, which can be triggered by inflammation and aging, as well as the toxins found in air pollution, pesticides, the smoke of forest fires and processed meats, interrupts the normal function of brain cells. Known as s-nitrosilation, this chemical change prevents brain cells from making new connections and, ultimately, results in cell death, the team discovered.
The investigation, published in the Proceedings of the National Academy of Sciences On February 27, 2025, he showed that the blockade of s-nitrosilation in a key cerebral protein reversed the signs of memory loss in Alzheimer’s mouse models and in nerve cells produced from human stem cells.
“We have revealed the molecular details of how pollutants can contribute to memory loss and neurodegenerative disease,” says Senior author and professor Stuart Lipton, MD, PHD, the STEP Family Foundation chair in Scripps Research and a clinical neurologist in the jolla, California. “This could lead to new medications that block these effects to better treat Alzheimer’s disease.”
More than two decades ago, Lipton first discovered S nitrosilation s, a chemical process by which a molecule related to nitric oxide (no) joins sulfur atoms (s) inside proteins (producing “SNO”), altering its function and forming what Lipton has called a “SNO storm” in the brain. It is not naturally within the body and occurs in response to electrical stimulation or inflammation, but it is also excessive in response to small particle material and nitrate -related compounds (designated PM2.5/NOX) present or triggered by climate change and air pollution related to the car, the smoke of wild fire, the pesticides and the processed meats. The research group and its Lipton colleagues have previously demonstrated that the aberrant reactions of s-nitrosilation contribute to some forms of cancer, autism, Alzheimer’s disease, Parkinson’s disease and other conditions.
In the new study, the Lipton group investigated the effect of s-nitrosilation on CRTC1 protein, which helps regulate genes that are critical to form and maintain connections between brain cells, an essential process for long-term learning and memory.
Using cultivated brain cells of mice and humans, researchers first confirmed that excess does not lead to CRTC1 s-nitrosilation. Then they discovered that this chemical modification prevented CRTC1 from joining another critical cerebral regulatory protein, CREB. As a result, other genes necessary to form connections between neurons could not be stimulated.
“This is a route that affects its memory and is directly involved in human Alzheimer’s disease,” says Lipton.
In fact, the team observed high levels of CRTC1 s-nitrosilation at an early stage of the disease in Alzheimer’s mice models and in human neurons derived from the stem cells of Alzheimer’s patients, which further supports the idea that chemical change plays a key role in the development of the symptoms of the disease.
Then, the research team genetically designed a version of CRTC1 that could no longer suffer s-nitrosilation, since the protein now lacked the amino acid containing sulfur (called cysteine) required for chemical reaction. In a Petri dish, the introduction of this modified version of CRTC1 in human nerve cells derived from Alzheimer’s patient cells avoided signs of disease, including the witness of nerve cell connections and the decrease in the survival of nerve cells. In Alzheimer’s mouse models, the re -enabled CRTC1 restored the activation of the genes necessary for memory formation and synaptic plasticity: the brain capacity to strengthen connections between neurons.
“We could completely rescue the molecular roads involved in the manufacture of new memories,” says Lipton. “It suggests that this is a pharmacological objective that could make a real difference in Alzheimer’s treatment and potentially other neurological diseases.”
Since environmental toxins, including car pollution and smoke from forest fires, can lead to high levels of non-brain, the new study strengthens the hypothesis that these toxins can accelerate the aging of the brain and Alzheimer’s brain through s-nitrosilation. The prevention of CRTC1 s-nitrosilation could be a viable route towards deceleration or prevent this type of brain damage related to Alzheimer’s, says Lipton.
The findings can also help explain why Alzheimer’s risk increases with age, he adds. Even without exposure to environmental toxins, aging leads to greater inflammation and higher levels of no, while the antioxidant defenses of the body weaken, which makes proteins more susceptible to the harmful reactions of s-nitrosilation.
“We are learning that nitrosylation s affects numerous proteins throughout the body, but reversing only some of these changes, such as CRTC1, could have a significant impact on memory function,” explains Lipton.
Your research group is now working to develop medications that can selectively block certain s-nitrosilation reactions, including those that affect CRTC1.
In Addition to Lipton, Authors of the Study, “S-Nitrosylation of Crtc1 in Alzheimer’s Disease Impairs Creb-Dependent Gene Expression Induced by Neuronal Activity,” Are First Author Xu Zhang, and Contribution Authors Roman Vlkolinsky, Chongyang Wu, Nima DOLATABADI, HENRY SCOTT, ANDREW ZHANG, MAYRA BLANCO, NHI LANG, JUAN PIÑA-CRESPO, TOMOHIRO NAKAMURA AND MARISA ROBERTO DE SCRIPPS REESARCH; and Olga Prikhodko, previously from the School of Graduates of UC San Diego in neurosciences.
This work was supported by funds from the Institute of Regenerative Medicine of California (EDUC4-12811) and the National Health Institutes (R01 AG061845, R61 NS122098, RF1 NS123298, R01 AA021491, U01 AA013498, AA029841, P60 AA00620 R0120620 R0120620 R0120620 R0120620 R0120620 R0120620 R01206420 R0120620 R0120620 R0120620 R0120 R0120620 ROT AA027700, R35 AG071734, RF1 AG057409, R56 AG065372, R01 AG078756 R01 AG056259, R01 D0488882, DP1 D041722).