Summary: A new study reveals a molecular link between fine particulate air pollution (PM2.5) and Lewy body dementia, a devastating neurodegenerative condition. By combining human epidemiological data and animal experiments, researchers showed that PM2.5 exposure triggers toxic clumps of alpha-synuclein in the brain, similar to those seen in patients.
Mice exposed to pollution developed brain atrophy, cognitive decline, and widespread protein clumps, while mice without alpha-synuclein showed no symptoms. The findings highlight pollution as a potential driver of dementia and a promising avenue for preventive strategies and drug development.
Key Facts:
- Pollution Link: PM2.5 exposure increases risk of Lewy body dementia by up to 17%.
- Protein Trigger: Airborne particles induce toxic alpha-synuclein clumps in mouse and human brains.
- Drug Target Potential: A newly identified pollution-related Lewy body strain may guide future treatments.
Source: Columbia University
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.
Funding:
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.
About this Lewy body dementia research news
Author: Stephanie Berger
Source: Columbia University
Contact: Stephanie Berger – Columbia University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Lewy body dementia promotion by air pollutants” by Xiaobo Mao et al. Science
Abstract
Lewy body dementia promotion by air pollutants
INTRODUCTION
Lewy body dementia (LBD), comprising dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) with dementia (PDD), is a devastating and increasingly prevalent neurodegenerative disorder.
Ambient PM2.5 is a recognized broad dementia risk factor; however, its specific role in initiating LBD, particularly its distinct pathological trajectory versus PD without dementia, remains unaddressed. This study systematically investigates this link.
RATIONALE
Pathologic α-synuclein (αSyn) is the defining neuropathological hallmark of LBD. A leading hypothesis posits that environmental neurotoxins, such as fine particulate matter (PM2.5), could trigger initial αSyn misfolding and propagation into the brain. However, epidemiological relationships between PM2.5 exposure and LBD versus PD subtypes lacked large-scale substantiation.
Whether PM2.5 can induce αSyn to form pathogenic strains that drive LBD’s specific clinical and pathological signatures remains unclear. Elucidating this environmental-molecular nexus is key to unravelling LBD pathogenesis and identifying targeted interventions. Our study aimed to dissect these fundamental mechanisms.
RESULTS
Convergent, multimodal evidence from large-scale human epidemiology, molecular, cellular, animal, and patient studies demonstrated a robust PM2.5-LBD link.
First, analysis of >56 million US Medicare beneficiaries revealed that chronic PM2.5 exposure was significantly associated with first hospitalizations for α-synucleinopathies.
A key finding was that the link between PM2.5 exposure and hospitalization risk was stronger for LBD (PDD and DLB) patients than for those with PD without dementia, implying a preferential vulnerability or pathogenic mechanism in LBD.
Second, we demonstrated an essential role of αSyn in PM2.5-related neurological disorders. Chronic PM2.5 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 PM2.5-induced detrimental effects, clearly establishing αSyn as an important mediator of this environmental neurotoxicity.
Third, we found that PM2.5 from diverse global sources (US, China, and Europe) induced conformational change in αSyn preformed fibrils (PFFs), inducing a distinct αSyn strain (PM-PFF). PM-PFF remained stable across passages and, compared with PFF, exhibited LBD-like pathogenic features, including accelerated aggregation, degradation resistance, enhanced propagation, and increased neurotoxicity, mimicking αSyn strains found in LBD.
When inoculated into humanized αSyn mice, this PM-PFF strain preferentially induced cognitive impairments, contrasting with the primarily motor deficits induced by PFF. Consistently, brain transcriptomic analyses revealed that both chronic PM2.5 exposure and PM-PFF inoculation in humanized αSyn mice elicited gene expression signatures that mirrored those of LBD (PDD and DLB) but not those of PD without dementia, underscoring an LBD-specific pathogenic axis.
CONCLUSION
This study provides evidence linking PM2.5 exposure to LBD. The neurotoxic effects of PM2.5 appear to be mediated by αSyn, with exposure generating a pathogenic strain (PM-PFF) that shares key properties with αSyn strains in human LBD.
In mice, this strain induced cognitive deficits and transcriptomic changes resembling those in LBD patients, distinct from those in PD without dementia. These findings identify an environmental mechanism contributing to LBD pathogenesis and underscores the role of αSyn.
The PM2.5-induced strain represents a potential target for therapeutic intervention. Collectively, these results emphasize the importance of further research into air pollution’s role in neurodegenerative diseases and its implications for public health strategies.
Source link
