A team of researchers found there is a possible molecular connection between air pollution and an increased risk of developing Lewy body dementia. The study builds on a decade of research linking exposure to fine particulate air pollution (PM2.5) -- from industrial activity, residential burning, wildfires, and vehicle exhaust—to a higher risk of developing these diseases. The findings add to a growing body of evidence indicating how environmental factors may trigger harmful protein changes in the brain that lead to neurodegeneration. The research is published in Science .
Lewy body diseases are a group of neurodegenerative disorders marked by the abnormal buildup of a protein, alpha-synuclein, in the brain. These clumps, known as Lewy bodies, are a hallmark of the conditions Parkinson's disease and Lewy body dementia.
In their new work, the team discovered that exposing mice to PM2.5 triggered the formation of abnormal alpha-synuclein clumps. These toxic protein clusters shared key structural and disease-related features with those found in the brains of patients with Lewy body dementia.
"We have identified a novel strain of Lewy bodies formed after exposure to air pollution," says corresponding author Xiaobo Mao, PhD, associate professor of neurology at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Institute for Cell Engineering. "By defining this strain, we hope to establish a specific target for future drugs aimed at slowing the progression of neurodegenerative diseases marked by Lewy bodies."
The research began with an analysis of hospital data from 56.5 million U.S. patients admitted between 2000 and 2014 with neurodegenerative diseases. The team focused on patients hospitalized for the first time with Lewy body-related conditions and used ZIP-code-level data to estimate their long-term exposure to PM2.5. The scientists found that each interquartile range increase of in PM2.5 concentration in these zip code areas resulted in a 17 percent higher risk of Parkinson's disease dementia and a 12 percent higher risk of dementia with Lewy bodies.
"This is among the first human epidemiological study to zero-in on a dementia subtype linked to Lewy bodies," said Xiao Wu, PhD, co-first author of the study and assistant professor of Biostatistics at Columbia University Mailman School of Public Health . "The statistical association we uncovered is even stronger than what previous studies found when lumping all Alzheimer's and related dementias together—highlighting Lewy body formation as a potentially pivotal pathway that warrants deeper biological investigation, says "We hope to inspire researchers to conduct both epidemiologic and molecular studies that focus on dementia subtypes linked to Lewy bodies."
Exploring the biological reason for this association between exposure to PM2.5 and Lew body dementia, the team of researchers exposed both normal mice and genetically modified mice lacking the alpha-synuclein protein to PM2.5 pollution every other day for a period of ten months.
"In normal mice, we saw brain atrophy, cell death, and cognitive decline—symptoms similar to those in Lewy body dementia," says study collaborator Ted Dawson, MD, PhD, the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases and director of the Johns Hopkins Institute for Cell Engineering. "But in mice lacking alpha-synuclein, the brain didn't exhibit any significant changes."
The researchers then studied mice with a human gene mutation (hA53T) linked to early-onset Parkinson's disease. After five months of PM2.5 exposure, these mice developed widespread pockets of alpha-synuclein and experienced cognitive decline. Observed through biophysical and biochemical analysis, these protein clumps were structurally distinct from those that form during natural aging.
The team also set out to determine whether air pollution effects varied by location. They found that mice exposed to separate samples of PM2.5 from China, Europe and the United States led to similar brain changes and development of alpha-synuclein pockets, suggesting that the harmful effects of PM2.5 may be broadly consistent across different regions.
The researchers say changes in gene expression in the brains of PM2.5-exposed mice were strikingly similar to those found in human patients with Lewy body dementia which indicate that pollution may not only trigger the build-up of toxic proteins but also drive disease-related gene expression changes in the human brain.
"We believe we've identified a core molecular link between PM2.5 exposure and the propagation of Lewy body dementia," Mao says.
While genetic factors play a significant role in neurodegenerative disease, the scientists say people can potentially control their exposure to pollution.
The next goal of the researchers is to determine which specific components in air pollution are driving these effects. Understanding that could help guide public health efforts to reduce harmful exposures and lower the risk of disease, notes the research team.
By identifying this novel strain of Lewy bodies formed after exposure to air pollution the authors of the study hope to establish a specific target for future drugs aimed at slowing the progression of neurodegenerative diseases marked by Lewy bodies.
See the paper for the full list of co-authors.
The research was supported by the National Institutes of Health (NIH RF1 AG079487, K01 ES036202, P20 AG093975, P30 ES009089, R01 ES030616, R01 AG066793, RF1 AG074372, RF1 AG080948), the Helis Foundation, the Parkinson's Foundation, the American Parkinson's Disease Association, the Freedom Together Foundation and the Department of Defense.
Columbia University Mailman School of Public Health
