Breathing polluted air, whether from city smog or wildfire smoke, is known to harm the lungs and heart. Now, new research sheds light on how these airborne toxins negatively impact the brain, potentially contributing to conditions like Alzheimer’s disease and autism. Scientists have discovered a process by which harmful substances can disrupt the normal function of brain cells, hindering their ability to connect and communicate, ultimately leading to cell damage. Their findings have been published in Proceedings of the National Academy of Sciences.
Previous research had already established a link between air pollution and conditions like asthma and heart disease. Epidemiological studies, which look at patterns of disease in populations, had also suggested that exposure to air pollution could increase the risk of developing brain conditions such as Alzheimer’s disease and autism. However, the precise biological mechanisms behind this connection remained unclear. Scientists wanted to understand exactly how breathing in polluted air could translate into harm within the brain. They aimed to uncover the specific chemical reactions that might be involved in this process, hoping to identify potential targets for future treatments and preventative measures.
The research team focused on a chemical process known as S-nitrosylation. This process occurs when a molecule related to nitric oxide attaches to sulfur atoms within proteins, changing how those proteins work. The scientists suspected that this process, which can be triggered by inflammation, aging, and exposure to toxins, might be a key factor in disrupting brain cell function.
Neuroscientist Stuart Lipton first discovered S-nitrosylation over two decades ago and had previously linked this reaction to various neurodegenerative diseases. He theorized that pollution-induced S-nitrosylation could interfere with proteins necessary for maintaining healthy brain function. To test this idea, his team focused on the protein CRTC1, which helps regulate genes critical for memory and learning.
“Epidemiologists have shown that air pollution from wildfires, automobile exhaust, and tobacco smoke releases small particulate material and nitric oxide-related molecules (PM2.5/NOx), which can contribute to the development of brain diseases like Alzheimer’s and autism,” explained Lipton, the Step Family Foundation Endowed Chair at Scripps Research and a clinical neurologist in La Jolla, California.
“Our group discovered the redox chemical reaction that underlies these events, termed protein S-nitrosylation, putting a nitrogen and oxygen onto a sulfur molecule in the amino acid cysteine, a building block of proteins. The abbreviation for the reaction is SNO – and there is a ‘SNO-storm in your brain’ due to air pollution. S-Nitrosylation of CRTC1 is one of those events, and it causally produced memory loss.”
Initially, the team examined brain cells grown in the laboratory to see if S-nitrosylation was happening to a protein called CRTC1. This protein is known to be important for brain cells to form new connections, a process essential for learning and memory. They exposed these cells to a molecule that causes S-nitrosylation and found that CRTC1 was indeed affected. They also observed this same effect in brain tissue from mouse models of Alzheimer’s disease, suggesting this process was relevant to the condition.
To understand exactly how S-nitrosylation impacted CRTC1, the scientists engineered a special version of the protein that could not undergo this chemical change. They then compared the behavior of normal CRTC1 with this modified version in both laboratory-grown cells and in living mouse models of Alzheimer’s disease. They used human nerve cells derived from stem cells of individuals with Alzheimer’s disease to further validate their findings in a human context.
The researchers discovered that S-nitrosylation of CRTC1 prevents it from properly interacting with another important protein in the brain called CREB. CREB is a key regulator of genes that are vital for brain cell connections, memory formation, and cell survival. In a healthy brain, CRTC1 and CREB work together to switch on these important genes. However, when CRTC1 is altered by S-nitrosylation, this partnership is disrupted.
The team found that S-nitrosylation doesn’t stop CRTC1 from moving to the cell nucleus, which is where it needs to be to interact with CREB. Instead, the chemical change directly interferes with CRTC1’s ability to bind to CREB once it’s in the nucleus. This blockage prevents the activation of genes necessary for maintaining healthy brain cell connections and supporting memory.
Importantly, when the scientists used the modified version of CRTC1 that could not be S-nitrosylated, they observed a partial reversal of memory problems in Alzheimer’s mouse models. Similarly, in human nerve cells grown from stem cells of Alzheimer’s patients, preventing S-nitrosylation of CRTC1 improved nerve cell function and survival. This suggests that blocking S-nitrosylation of CRTC1 could be a potential way to treat or prevent some of the brain changes associated with Alzheimer’s disease and possibly other related conditions.
Looking ahead, this research opens up new avenues for developing treatments for brain diseases linked to environmental factors. The discovery that blocking S-nitrosylation of CRTC1 can improve brain function suggests that targeting this chemical process could be a promising therapeutic strategy. Scientists could explore the development of drugs that specifically prevent S-nitrosylation or reverse its effects, potentially offering new ways to protect the brain from the harmful impacts of air pollution, pesticides, processed meats, and other environmental toxins.
“We are developing drugs to combat this,” Lipton said.
The study, “S-Nitrosylation of CRTC1 in Alzheimer’s disease impairs CREB-dependent gene expression induced by neuronal activity,” was authored by Xu Zhang, Roman Vlkolinsky, Chongyang Wu, Nima Dolatabadi, Henry Scott, Olga Prikhodko, Andrew Zhang, Mayra Blanco, Nhi Lang, Juan Piña-Crespo, Tomohiro Nakamura , Marisa Roberto, and Stuart A. Lipton.
