Air pollution contributes to nearly 7 million premature deaths each year, and its effects reach far beyond the lungs. Breathing smoke from wildfires or from cities caused by automobiles not only increases the risk of asthma and heart disease—it can also contribute to brain disorders as diverse as Alzheimer’s disease and autism.
Scientists at Scripps Research discovered how a chemical alteration in the brain—which can be triggered by inflammation and aging, as well as by toxins found in air pollution, pesticides, wildfire smoke, and processed meats—disrupts the normal function of brain cells. Known as S-nitrosylation, this chemical modification prevents brain cells from forming new connections and ultimately results in cell death, the team found.
The investigation, published in the Proceedings of the National Academy of Sciences, showed that blocking S-nitrosylation in a key brain protein partially reversed memory-loss signals in rat models of Alzheimer’s disease and in neurons derived from human stem cells.
“We have revealed the molecular details of how pollutants can contribute to memory loss and to neurodegenerative diseases,” says senior author and Professor Stuart Lipton, MD, PhD, the Step Family Foundation Endowed Chair at Scripps Research and a clinical neurologist in La Jolla, California. “This could lead to new drugs that block these effects to better treat Alzheimer’s disease,” he adds.
More than two decades ago, Lipton first discovered S-nitrosylation, a chemical process by which a molecule related to nitric oxide (NO) binds to sulfur atoms (S) within proteins (producing “SNO”), altering their function and forming what Lipton called “SNO-STORM” in the brain.
NO is naturally present in the body and is produced in response to electrical stimuli or inflammation—but it also forms in excess in response to fine particles and nitrate-related compounds (designated PM2.5/NOx) present or triggered by climate change and automobile-related air pollution, wildfire smoke, pesticides, and processed meats.
The Lipton research group and colleagues had previously shown that aberrant S-nitrosylation reactions contribute to some forms of cancer, autism, Alzheimer’s disease, Parkinson’s disease and other diseases.
In the new study, Lipton’s group investigated the effect of S-nitrosylation on the CRTC1 protein, which helps regulate genes that are critical for the formation and maintenance of connections between brain cells, a process essential for learning and long-term memory.
Using cultures of brain cells from mice and humans, the researchers began by confirming that excess NO leads to S-nitrosylation of CRTC1. They then found that this chemical modification prevented CRTC1 from binding to another critical brain regulatory protein, CREB. As a result, other genes necessary for the formation of connections between neurons were not stimulated.
“This is a pathway that affects memory and is directly implicated in human Alzheimer’s disease,” says Lipton.
In fact, the team observed elevated levels of S-nitrosylated CRTC1 at an early stage of the disease in Alzheimer’s model mice and in neurons derived from stem cells of patients with Alzheimer’s, further supporting the idea that the chemical alteration plays a fundamental role in the development of the disease’s symptoms.
Subsequently, the research team genetically engineered a version of CRTC1 that could no longer undergo S-nitrosylation, since the protein now lacked the sulfur-containing amino acid (called cysteine) needed for the chemical reaction.
In a Petri dish, introducing this modified version of CRTC1 into human neurons derived from the stem cells of Alzheimer’s patients prevented the disease signals, including the weakening of connections between neurons and the decreased survival of neurons.
In Alzheimer’s model mice, the redesigned CRTC1 restored the activation of genes necessary for memory formation and synaptic plasticity—the brain’s ability to strengthen connections between neurons.
“We were able to almost completely recover the molecular pathways involved in creating new memories,” says Lipton. “This suggests that it is a druggable target and could make a real difference in treating Alzheimer’s disease and, potentially, other neurological diseases,” he adds.
Because environmental toxins, including automobile pollution and wildfire smoke, can lead to elevated NO levels in the brain, the new study reinforces the hypothesis that these toxins can accelerate brain aging and Alzheimer’s disease through S-nitrosylation. Blocking S-nitrosylation of CRTC1 could be a viable route to slow or prevent this type of brain injury related to Alzheimer’s disease, Lipton states.
The results may also help explain why the risk of Alzheimer’s increases with age, he adds. Even without exposure to environmental toxins, aging leads to increased inflammation and higher NO levels, while the body’s antioxidant defenses weaken, making proteins more susceptible to harmful S-nitrosylation reactions.
“We are learning that S-nitrosylation affects numerous proteins across the body, but reversing just some of these alterations—such as those affecting CRTC1—could have a meaningful impact on memory function,” Lipton explains.
His research group is now working on developing drugs that can selectively block certain S-nitrosylation reactions, including those affecting CRTC1.
