A common chemical from car tires might disrupt human brain cells and promote dementia

A recent study suggests that a common chemical byproduct created by the breakdown of automobile tires might interfere with the molecular machinery of human brain cells, potentially increasing the risk of Alzheimer’s disease. By utilizing advanced computational models, scientists mapped how this environmental pollutant interacts with specific genes and proteins associated with neurodegeneration. The findings were published in the journal Open Medicine.

To make tires durable and prevent them from cracking, manufacturers add a chemical known as 6PPD. When microscopic particles of tire rubber wear off on the road and react with ozone gas in the air, they transform into a new chemical called 6PPD-quinone. This secondary pollutant washes into waterways, settles in road dust, and has been frequently detected in human urine and blood samples.

Previous research indicates that 6PPD-quinone is highly toxic to certain aquatic life, such as salmon. It also has the ability to cross the blood-brain barrier in mice. The blood-brain barrier is a highly selective membrane that protects the brain from harmful substances in the bloodstream. The ability of a pollutant to bypass this shield provides evidence that it might directly affect human brain health.

The molecular structure of 6PPD-quinone suggests it can trigger oxidative stress, a condition where unstable oxygen molecules damage cellular structures. It also tends to provoke neuroinflammation, which is a state of chronic swelling and immune system overactivity in the brain. Both oxidative stress and neuroinflammation are defining features of Alzheimer’s disease, the most common form of dementia worldwide.

Because this chemical can reach the brain and cause cellular damage similar to what happens in dementia, researchers Chun Zhang from Chongqing Three Gorges Medical College and Jingqi Zhang from Chengdu University of Traditional Chinese Medicine wanted to map the exact molecular pathways connecting the two. They designed a study to systematically explore how exposure to this specific tire pollutant might alter human genetics and protein functions.

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The researchers began by predicting which human proteins 6PPD-quinone might interact with in the body. They used three distinct pharmacological databases to gather a list of potential chemical targets. Through this software, they identified over one hundred potential interaction points within human biology.

Next, they collected a massive catalog of genes associated with Alzheimer’s disease from clinical and genetic databases. By comparing the list of chemical targets with the list of disease genes, the authors identified 92 overlapping targets. This overlap points to a shared biological network between the environmental pollutant and the neurodegenerative disease.

To narrow down this list, the scientists built a protein-protein interaction network. This type of analysis maps how different proteins communicate and work together within a cell. By filtering out the less active proteins, they isolated 23 core target genes that act as central communication hubs.

The authors then analyzed where these 23 core genes are most active in the human body. They found a high concentration of gene expression in specific brain regions, including the cerebral cortex and the basal ganglia. These are areas heavily involved in memory and movement, and they are notoriously vulnerable to Alzheimer’s disease.

To see how these specific genes behave in real patients, the researchers examined two genetic datasets containing post-mortem brain tissue samples. The first dataset included 12 patients with Alzheimer’s disease, 10 elderly healthy controls, and 8 young healthy controls. The second dataset included 44 patients with the disease and 46 healthy controls.

They found that the expression levels of the core genes were significantly altered in the diseased brains. Genes responsible for managing inflammation and cellular damage were abnormally active or suppressed compared to the healthy brain samples. This provided real-world biological backing to their computer-generated predictions.

The researchers then trained an artificial intelligence model using the genetic data from the 90 individuals in the second dataset. They wanted to determine which specific genes could best predict whether a brain sample belonged to an Alzheimer’s patient or a healthy individual. The machine learning model identified five specific genes as the strongest diagnostic predictors.

Among these top predictors were genes known as NFKB1, which manages the body’s inflammatory response, and NFE2L2, which normally protects cells from oxidative damage. The model also highlighted kinase genes, which produce enzymes that act like control switches for cell behavior. In neurodegenerative conditions, faulty kinase switches can lead to the dangerous tangling of proteins inside brain cells.

To look for cause-and-effect relationships, the scientists analyzed genetic data from 488,285 individuals using a technique called Mendelian randomization. This method uses natural genetic variations to see if a specific biological factor directly causes a disease. The analysis suggested that genetic variations altering the activity of the NFKB1 gene in the brain might directly influence a person’s risk of developing Alzheimer’s disease.

The authors also used a computational technique called molecular docking to simulate how the 6PPD-quinone molecule physically fits into these specific human proteins. Proteins have complex, three-dimensional shapes with specific pockets, and molecular docking tests how well a foreign molecule fits into those pockets. The computer simulations showed that the tire pollutant binds strongly to several of the core proteins, potentially blocking them from performing their normal functions.

Finally, the scientists ran a computer simulation on 163,824 individual brain cells to see what would happen if these key genes were disrupted. They focused on microglia, which are the primary immune cells in the central nervous system. These cells act as the brain’s garbage collectors, cleaning up damaged cells and managing local immune responses.

The simulation predicted that interfering with these core genes would disrupt how the microglia produce energy and respond to cellular damage. This predicted disruption was especially pronounced in cells that simulated an Alzheimer’s disease environment. The findings suggest that the pollutant could worsen existing neurological issues by crippling the brain’s natural cleanup crew.

While this study provides a detailed theoretical framework for how a common environmental pollutant might harm the brain, it relies primarily on computer predictions and existing datasets. The researchers note that computer simulations of chemical binding do not guarantee that the exact same biological reactions will occur in a living human body. Experimental testing is necessary to confirm the physical interactions.

Another limitation is the reliance on brain tissue samples from late-stage Alzheimer’s patients. These samples represent the end stage of a long disease process, which might hide the early molecular changes caused by initial exposure to the pollutant. It is difficult to determine exactly when the chemical begins to alter brain chemistry in a real-world scenario.

The authors suggest that future research should involve laboratory experiments on living cells and animal models. Scientists need to expose animals to low doses of 6PPD-quinone over long periods to confirm if the chemical consistently crosses the blood-brain barrier and triggers these specific genetic changes. This would provide concrete evidence of the pollutant’s neurotoxic effects.

Epidemiological studies are also required to track human exposure to tire pollution over extended periods of time. Tracking populations heavily exposed to traffic pollution could help confirm whether everyday contact with this chemical actually translates to higher rates of dementia. Such studies would help public health officials understand the true scope of the risk.

The study, “6PPD-quinone exposure and Alzheimer’s disease: insights from integrative network pharmacology, transcriptomics, machine learning, and molecular docking,” was authored by Chun Zhang and Jingqi Zhang.