La Jolla, California – Air pollution, a major environmental health concern that contributes to nearly 7 million premature deaths annually, may have far-reaching effects beyond respiratory diseases. New research from Scripps Research reveals that pollutants in the air, including wildfire smoke, automobile smog, and pesticides, may also play a significant role in the development of brain diseases like Alzheimer’s.
The study, published in the Proceedings of the National Academy of Sciences, identifies a chemical change in the brain—known as S-nitrosylation—that may be a key factor in the development of Alzheimer’s disease. This chemical modification, which can be triggered by inflammation, aging, and toxins found in pollutants, disrupts normal brain cell function. The research shows that S-nitrosylation can prevent brain cells from making new connections, eventually leading to cell death.
Stuart Lipton, MD, PhD, the senior author of the study and professor at Scripps Research, explains that S-nitrosylation occurs when a molecule related to nitric oxide (NO) binds to sulfur (S) atoms in proteins, causing them to malfunction. Lipton, who first discovered this process over two decades ago, refers to the phenomenon as a “SNO-STORM” in the brain. While nitric oxide naturally forms in the body in response to electrical stimulation or inflammation, it can also be produced in excess due to environmental pollutants, such as particulate matter (PM2.5), nitrate-related compounds (NOx), and toxins found in processed meats.
In this study, Lipton’s team focused on the protein CRTC1, which regulates genes crucial for maintaining and forming connections between brain cells—a process critical for memory and learning. They discovered that when excess nitric oxide triggers S-nitrosylation, it prevents CRTC1 from binding to another protein, CREB, which in turn fails to stimulate genes required for neuronal connections.
“We’ve revealed the molecular mechanisms by which environmental toxins contribute to memory loss and neurodegenerative diseases like Alzheimer’s,” says Lipton. “This could ultimately lead to new therapies that block these effects and provide better treatments for Alzheimer’s.”
The research demonstrated high levels of S-nitrosylated CRTC1 in both early-stage Alzheimer’s mouse models and human neurons derived from stem cells of Alzheimer’s patients, supporting the role of this chemical modification in the disease’s development. In their experiments, the team genetically engineered a version of CRTC1 that could not undergo S-nitrosylation. Introducing this modified protein into human nerve cells derived from Alzheimer’s patients’ stem cells prevented cellular damage, including the loss of nerve cell connections and increased cell survival.
In Alzheimer’s mouse models, the engineered version of CRTC1 helped restore the activation of genes necessary for memory formation and synaptic plasticity, which is the brain’s ability to strengthen connections between neurons. Lipton and his colleagues noted that this modification significantly reversed the molecular pathways that are crucial for creating new memories, indicating that blocking S-nitrosylation could potentially treat Alzheimer’s and other neurological diseases.
These findings also shed light on the link between environmental toxins, such as automobile pollution and wildfire smoke, and accelerated brain aging. Lipton suggests that these toxins could heighten the risk of Alzheimer’s through increased levels of nitric oxide and S-nitrosylation in the brain. Moreover, the research supports the hypothesis that the risk of Alzheimer’s increases with age, as aging leads to inflammation and higher nitric oxide levels, making proteins more vulnerable to harmful S-nitrosylation.
“The findings point to the potential for reversing some of the harmful effects of S-nitrosylation, specifically those affecting CRTC1, to improve memory function,” explains Lipton. His team is now working on developing drugs that can selectively block S-nitrosylation reactions, particularly those involving CRTC1, which could pave the way for new treatments for Alzheimer’s and other neurodegenerative diseases.
This research underscores the urgent need to address the health risks of air pollution and environmental toxins, not just for respiratory and heart health, but also for their profound impacts on brain function and cognitive decline.
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