How Air Pollution and Smoke from Wildfires Can Contribute to Memory Loss in Alzheimer’s Disease

Air pollution contributes to nearly 7 million premature deaths each year, and its effects go well beyond the lungs. Breathing smoke from wildfires or smog caused by car traffic in cities not only increases the risk of asthma and heart disease, but can also contribute to brain disorders as diverse as Alzheimer’s and autism. Scientists at Scripps Research have discovered how a chemical alteration in the brain – which can be triggered by inflammation and aging processes, as well as by toxins in air pollution, pesticides, smoke from wildfires and processed meats – disrupts the normal function of brain cells.

This chemical change, known as S-nitrosylation, prevents brain cells from forming new connections and ultimately leads to cell death, the team discovered. The study, published in Proceedings of the National Academy of Sciences on February 27, 2025, showed that blocking S-nitrosylation in a key brain protein partially reversed the signs of memory loss in Alzheimer’s mouse models and in nerve cells made from human stem cells.

Air Pollution and the Effects on the Brain

“We have uncovered the molecular details of how pollutants can contribute to memory loss and neurodegenerative diseases,” says senior author and Professor Stuart Lipton, MD, Dr. phil., holder of 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 in which a molecule related to nitric oxide (NO) binds to sulfur (S) atoms in proteins (creating “SNO”), altering their function and creating what Lipton calls an “SNO-STORM” in the brain. Nitric oxide occurs naturally in the body and is produced in response to electrical stimulation or inflammatory conditions – but it is also produced in excess in response to small particles and nitrate-related compounds (referred to as PM2.5/NOx), which are present in and triggered by climate change and car-based air pollution, smoke from wildfires, pesticides, and processed meats. The research group of Lipton and colleagues have previously demonstrated that aberrant S-nitrosylation reactions contribute to some forms of cancer, autism, Alzheimer’s, Parkinson’s, and other diseases.

High Levels of S-Nitrosylated CRTC1 in Alzheimer’s Mouse Models

In the new study, Lipton’s group examined the effects of S-nitrosylation on the protein CRTC1, which helps regulate genes 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 nitric oxide leads to the S-nitrosylation of CRTC1. They then found that this chemical modification prevented the binding of CRTC1 to another important brain regulatory protein, CREB. As a result, other genes necessary for forming connections between neurons could not be stimulated. This is one pathway that impacts memory and is directly linked to human Alzheimer’s disease.

In fact, the team observed high levels of S-nitrosylated CRTC1 in early-stage disease in Alzheimer’s mouse models and in human neurons derived from stem cells of Alzheimer’s patients, further supporting the notion that the chemical modification plays a key role in the development of disease symptoms. Next, the research team engineered a genetically modified version of CRTC1 that could not be S-nitrosylated because the protein lacked the sulfur-containing amino acid (cysteine) required for the chemical reaction. In a petri dish, introducing this modified version of CRTC1 into human nerve cells derived from stem cells of Alzheimer’s patients prevented signs of the disease, including the dying off of nerve cell connections and reduced nerve cell survival. In Alzheimer’s mouse models, the engineered CRTC1 restored the activation of genes required for memory formation and synaptic plasticity – the brain’s ability to strengthen connections between neurons.

Development of New Drugs

The researchers were able to almost completely rescue the molecular signaling pathways involved in the formation of new memories. This suggests that this is a drug-targettable pathway that could make a real difference in the treatment of Alzheimer’s and possibly other neurological diseases. Since environmental toxins, including automobile exhaust and smoke from wildfires, can lead to increased NO levels in the brain, the new study supports the hypothesis that these toxins can accelerate brain aging and Alzheimer’s disease through S-nitrosylation.

Preventing the S-nitrosylation of CRTC1 could be a viable way to slow or prevent this type of Alzheimer’s-related brain damage. The findings may also explain why the risk of Alzheimer’s increases with age, according to the researchers. Even in the absence of environmental toxin exposure, aging leads to increased production of inflammation and nitric oxide, while the body’s antioxidant defenses weaken, leaving proteins more vulnerable to harmful S-nitrosylation reactions. Lipton’s research group is now working on the development of drugs that can selectively block certain S-nitrosylation reactions, including those that affect CRTC1.