Air pollution may contribute to the development of Alzheimer’s disease
A chemical reaction that is increased in response to air pollution may contribute to the development of Alzheimer’s disease.
Air pollution is responsible for nearly 7 million premature deaths each year, but its harmful effects extend far beyond the lungs. Researchers from Scripps Research (CA, USA) led by Stuart Lipton have discovered that a chemical reaction – S-nitrosylation – is increased in response to toxins and alters a key protein involved in learning and long-term memory. Blocking the reaction reversed signs of Alzheimer’s in mice and stem cell models, indicating the reaction could be a target for Alzheimer’s drug development.
Nitric oxide (NO) is found naturally in the body and is produced in response to electrical stimulation and inflammation; however, certain triggers like air pollution, pesticides and processed meats can cause excess NO. For over two decades, Lipton has been investigating a chemical process called S-nitrosylation, a post-translational modification whereby an NO-related molecule binds to sulfur atoms in proteins to produce ‘SNO’, altering protein function and creating what Lipton calls a ‘SNO-STORM’.
In this study, the group focused on S-nitrosylation of cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1), a protein that helps regulate genes essential for forming and maintaining connections between brain cells – crucial for learning and long-term memory – and that is dysregulated in Alzheimer’s disease.
Using cultured brain cells from mice and humans, the researchers confirmed that excess NO leads to S-nitrosylation of CRTC1, forming SNO-CRTC1. They then discovered this prevents CRTC1 binding with CREB, another key regulatory protein in the brain, which diminishes the activity-dependent gene expression mediated by the CRTC1/CREB pathway.
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The team found high levels of SNO-CRTC1 at an early disease stage in Alzheimer’s mouse models as well as in human-induced pluripotent stem cells (hiPSCs) derived from people with Alzheimer’s, further suggesting that S-nitrosylation plays a role in the development of Alzheimer’s.
The researchers identified sulfur-containing Cys216 of CRTC1 as the primary target of S-nitrosylation. They used the CRISPR/Cas9 system to engineer a version of CRTC1 that lacks Cys216, preventing it from undergoing S-nitrosylation.
Introducing modified CRTC1 into Alzheimer’s Disease-derived hiPSCs prevented signs of Alzheimer’s, including withering of neuron connections and decreased neuron survival. In Alzheimer’s mouse models, the engineered protein restored the activation of memory-related genes and improved synaptic plasticity.
“We could nearly completely rescue molecular pathways involved in making new memories,” explained Lipton. “It suggests that this is a druggable target that could make a real difference in treating Alzheimer’s and potentially other neurological diseases.”
The study strengthens the hypothesis that stimuli that increase NO levels in the brain, such as air pollution and wildfire smoke, can accelerate brain aging and the development of Alzheimer’s through S-nitrosylation. Aging leads to increased inflammation and NO levels, so the study could also help explain why Alzheimer’s risk increases with age.
The team is now looking at developing drugs that can selectively block certain 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,” concluded Lipton.
