Studies headed by researchers at Johns Hopkins Medicine have uncovered a possible molecular connection between air pollution and an increased risk of developing Lewy body dementia (LBD). The team discovered that exposing mice to fine particulate air pollution (PM_2.5) triggered formation of an abnormal alpha-synuclein (αSyn) strain, PM_2.5–induced preformed fibril (PM-PFF). These toxic protein clusters shared key structural and disease-related features with those found in the brains of patients with Lewy body dementia.

The findings add to a growing body of evidence indicating how environmental factors may trigger harmful protein changes in the brain. These changes lead to neurodegeneration and build on a decade of research linking exposure to fine particulate air pollution to a higher risk of developing these diseases.

“We have identified a novel strain of Lewy bodies formed after exposure to air pollution,” said 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.”

Mao and colleagues described their findings in Science, in a paper titled “Lewy body dementia promotion by air pollutants,” in which they concluded “Taken together, these findings suggest a powerful link between PM_2.5 exposure, the formation of LBD-like αSyn strains, and the development of LBD, highlighting the role of environmental factors in disease progression.”

Lewy body diseases are a group of neurodegenerative disorders marked by abnormal build-up of the protein, alpha-synuclein, in the brain. These clumps, known as Lewy bodies, are a hallmark of the conditions Parkinson’s disease (PD) with dementia (PDD) and Lewy body dementia. However, the team noted in its report, while emerging evidence suggest that urban and roadside air pollution are contributing factors to dementia, “The link between air pollution and LBD is unknown.”

The team proposed that that air pollutants, particularly PM_2.5, may contribute to development of LBD by promoting the formation of LBD-like αSyn strains. To test their hypothesis the team evaluated epidemiological evidence in parallel with the results of experiments testing the effects of PM_2.5 exposure in mice, and analysis of αSyn strains in the cerebrospinal fluid of LBD patients. The also carried out transcriptomic analysis of PM_2.5-exposed mice, and animals inoculated with PM_2.5-induced αSyn, and compared the results with previously published data from LBD brain tissues.

The researchers first analyzed hospital data from 56.5 million U.S. patients admitted between 2000 and 2014 with neurodegenerative diseases. They focused on patients hospitalized for the first time with Lewy body-related conditions, and used data from the individuals’ ZIP codes to estimate their long-term exposure to PM_2.5. The scientists found that each interquartile range increase in PM_2.5 concentration in these ZIP code areas resulted in a 17% higher risk of Parkinson’s disease dementia and a 12% higher risk of dementia with Lewy bodies.

“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,” said Xiao Wu, PhD, a co-first and co-corresponding author of the study, and assistant professor of biostatistics at Columbia University Mailman School of Public Health.

Exploring the biological reason for this association between exposure to PM_2.5 and Lewy body dementia, the researchers then exposed both normal mice, and mice genetically modified to lack the alpha-synuclein protein (αSyn^−/− animals), to PM_2.5 pollution every other day for a period of 10 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 Institute for Cell Engineering. “But in mice lacking alpha-synuclein, the brain didn’t exhibit any significant changes.” The authors added, “PM_2.5 exposure generated a highly pathogenic αSyn strain, PM_2.5–induced preformed fibril (PM-PFF), with enhanced proteinase K resistance and neurotoxicity, resembling αSyn LBD strains.” Noted Mao, “We believe we’ve identified a core molecular link between PM_2.5 exposure and the propagation of Lewy body dementia.”

In their research article summary the team further stated, “Chronic PM_2.5 exposure in wild-type (WT) mice induced brain atrophy, cognitive deficits, and widespread αSyn pathology in the brain and peripheral organs (gut, lungs) as well as concomitant tau pathology. Genetic ablation of αSyn conferred strong protection against these PM_2.5-induced detrimental effects, clearly establishing αSyn as an important mediator of this environmental neurotoxicity.”

The researchers then studied mice with a human gene mutation (hA53T) linked to early-onset Parkinson’s disease. “This model allowed us to compare the αSyn strain formed due to natural aging with those induced by PM_2.5 exposure,” they explained. After five months of PM_2.5 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 researchers also set out to determine whether air pollution effects varied by location. They found that mice exposed to separate samples of PM_2.5 from China, Europe, and the United States led to similar brain changes and development of alpha-synuclein pockets. “This suggests that the harmful effects of PM_2.5 may be broadly consistent across different regions,” said first author Haiqing Liu, PhD, a postdoctoral fellow at Johns Hopkins University School of Medicine.

The researchers say changes in gene expression in the brains of PM_2.5-exposed mice were strikingly similar to those found in human patients with Lewy body dementia. “This suggests that pollution may not only trigger the build-up of toxic proteins but also drive disease-related gene expression changes in the human brain,” said Shizhong Han, PhD, lead investigator at the Lieber Institute and for Brain Development and an associate professor of psychiatry and behavioral sciences at the school of medicine.

The authors further stated, “Transcriptomic analyses revealed shared responses between PM_2.5-exposed mice and LBD patients, underscoring PM_2.5’s role in LBD and stressing the need for interventions to reduce air pollution and its associated neurological disease burden.”

While genetic factors play a significant role in neurodegenerative disease, the researchers say people can potentially control their exposure to pollution. “Our next goal is to figure out which specific components in air pollution are driving these effects,” says Xiaodi Zhang, PhD, a first author of the study and postdoctoral fellow at the school of medicine. “Understanding that could help guide public health efforts to reduce harmful exposures and lower the risk of disease.”

Added Wu, “We hope to inspire researchers to conduct both epidemiologic and molecular studies that focus on dementia subtypes linked to Lewy bodies.” The team further concluded, “Collectively, these results emphasize the importance of further research into air pollution’s role in neurodegenerative diseases and its implications for public health strategies.”