How air pollution and wildfire smoke may contribute to memory loss in Alzheimer’s disease

LA JOLLA, CA—Air pollution contributes to nearly 7 million premature deaths each year, and its effects go far beyond the lungs. Breathing in wildfire smoke or automobile-related city smog doesn’t just increase the risk of asthma and heart disease—it may also contribute to brain diseases as diverse as Alzheimer’s and autism.

Scientists at Scripps Research have discovered how a chemical change in the brain—which can be triggered by inflammation and aging as well as toxins found in air pollution, pesticides, wildfire smoke and processed meats—disrupts normal brain cell function. Known as S-nitrosylation, this chemical change prevents brain cells from making new connections and ultimately results in cellular death, the team discovered.

The research, published in the Proceedings of the National Academy of Sciences on February 27, 2025, showed that blocking S-nitrosylation in a key brain protein partially reversed signs of memory loss in Alzheimer’s mouse models and in nerve cells produced from human stem cells.

“We’ve 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 Endowed Chair at Scripps Research and a clinical neurologist in La Jolla, California. “This could ultimately lead to new drugs that block these effects to better treat Alzheimer’s disease.”

More than two decades ago, Lipton first discovered S-nitrosylation, a chemical process whereby a molecule related to nitric oxide (NO) binds to sulfur (S) atoms within proteins (producing “SNO”), altering their function and forming what Lipton has called a “SNO-STORM” in the brain. NO is found naturally within the body and produced in response to electrical stimulation or inflammation—but it also forms in excess in response to small particulate material and nitrate-related compounds (designated PM2.5/NOx) present in or triggered by climate change and automobile-related air pollution, wildfire smoke, pesticides, and processed meats. Lipton’s research group and colleagues have previously demonstrated that aberrant S-nitrosylation reactions contribute to some forms of cancer, autism, Alzheimer’s disease, Parkinson’s disease and other conditions.

In the new study, Lipton’s group investigated the effect of S-nitrosylation on the protein CRTC1, which helps regulate genes that are critical for forming and maintaining connections between brain cells, an essential process for learning and long-term memory.

Using cultured brain cells from mice and humans, the researchers first confirmed that excess NO leads to S-nitrosylation of CRTC1. They then discovered that this chemical modification prevented CRTC1 from binding to another critical brain regulatory protein, CREB. As a result, other genes necessary for forming connections between neurons failed to be stimulated.

“This is a pathway that affects your memory and is directly implicated in human Alzheimer’s disease,” says Lipton.

Indeed, the team observed high levels of S-nitrosylated CRTC1 at an early stage of disease in Alzheimer's mouse models and in human neurons derived from stem cells of Alzheimer’s patients, further supporting the idea that the chemical change plays a key role in the development of disease symptoms.

Next, the research team genetically engineered a version of CRTC1 that could no longer undergo S-nitrosylation, as the protein now lacked the sulfur-containing amino acid (called cysteine) required for the chemical reaction. In a petri dish, introducing this modified version of CRTC1 into human nerve cells derived from Alzheimer’s patient stem cells prevented signs of disease, including withering of nerve cell connections and decreased nerve cell survival. In Alzheimer’s mouse models, the re-engineered CRTC1 restored the activation of genes required for memory formation and synaptic plasticity—the brain’s ability to strengthen connections between neurons.

“We could nearly completely rescue molecular pathways involved in making new memories,” says Lipton. “It suggests that this is a druggable target that could make a real difference in treating Alzheimer’s and potentially other neurological diseases.”

Given that environmental toxins, including automobile pollution and wildfire smoke, can result in elevated NO levels in the brain, the new study strengthens the hypothesis that these toxins can accelerate brain aging and Alzheimer’s through S-nitrosylation. Preventing S-nitrosylation of CRTC1 could be a viable pathway toward slowing or preventing this type of Alzheimer’s-related brain damage, says Lipton.

The findings may also help explain why Alzheimer’s risk 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’re learning that S-nitrosylation affects numerous proteins throughout the body, but reversing just some of these changes—like those on CRTC1—could have a significant impact on memory function," explains Lipton.

His research group is now working to develop drugs that can selectively block certain S-nitrosylation reactions, including those affecting 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 contributing authors Roman Vlkolinsky, Chongyang Wu, Nima Dolatabadi, Henry Scott, Andrew Zhang, Mayra Blanco, Nhi Lang, Juan Piña-Crespo, Tomohiro Nakamura and Marisa Roberto of Scripps Research; and Olga Prikhodko, formerly of the UC San Diego Graduate School in Neurosciences.

This work was supported by funding from the California Institute for Regenerative Medicine (EDUC4-12811), and the National Institutes of Health (R01 AG061845, R61 NS122098, RF1 NS123298, R01 AA021491, U01 AA013498, AA029841, P60 AA006420 R01 AA027700, R35 AG071734, RF1 AG057409, R56 AG065372, R01 AG078756, R01 AG056259, R01 DA048882, DP1 DA041722).

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