Lewy body dementia promotion by air pollutants

Xiaodi Zhang; Haiqing Liu; Xiao Wu; Longgang Jia; Kundlik Gadhave; Lena Wang; Kevin Zhang; Hanyu Li; Rong Chen; Ramhari Kumbhar; Ning Wang; Chantelle E Terrillion; Bong Gu Kang; Bin Bai; Minhan Park; Ma Cristine Faye Denna; Shu Zhang; Wenqiang Zheng; Denghui Ye; Xiaoli Rong; Liu Yang; Lili Niu; Han Seok Ko; Weiyi Peng; Lingtao Jin; Mingyao Ying; Liana S Rosenthal; David W Nauen; Alex Pantelyat; Mahima Kaur; Kezia Irene; Liuhua Shi; Rahel Feleke; Sonia García-Ruiz; Mina Ryten; Valina L Dawson; Francesca Dominici; Rodney J Weber; Xuan Zhang; Pengfei Liu; Ted M Dawson; Shizhong Han; Xiaobo Mao

doi:10.1126/science.adu4132

Lewy body dementia promotion by air pollutants

Science. 2025 Sep 4;389(6764):eadu4132. doi: 10.1126/science.adu4132. Epub 2025 Sep 4.

Authors

Xiaodi Zhang^#^{1

2

3}, Haiqing Liu^#^{1

2}, Xiao Wu^#⁴, Longgang Jia^#^{1

2}, Kundlik Gadhave^{1

2}, Lena Wang^{1

2}, Kevin Zhang^{1

2}, Hanyu Li^{1

2}, Rong Chen^{1

2}, Ramhari Kumbhar^{1

2}, Ning Wang^{1

2}, Chantelle E Terrillion⁵, Bong Gu Kang^{1

2}, Bin Bai⁶, Minhan Park⁶, Ma Cristine Faye Denna⁶, Shu Zhang^{1

2}, Wenqiang Zheng^{1

2}, Denghui Ye^{1

2}, Xiaoli Rong^{1

2}, Liu Yang^{1

2}, Lili Niu^{1

2

3}, Han Seok Ko^{1

2}, Weiyi Peng⁷, Lingtao Jin⁸, Mingyao Ying^{2

9}, Liana S Rosenthal², David W Nauen¹⁰, Alex Pantelyat², Mahima Kaur¹¹, Kezia Irene¹¹, Liuhua Shi¹², Rahel Feleke¹³, Sonia García-Ruiz^{14

15

16}, Mina Ryten^{14

15

16}, Valina L Dawson^{1

2

3

17

18}, Francesca Dominici¹¹, Rodney J Weber⁶, Xuan Zhang¹⁹, Pengfei Liu⁶, Ted M Dawson^{1

2

3

18

20

21}, Shizhong Han^{22

5

23}, Xiaobo Mao^{1

2

3

21

24}

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
⁴ Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Earth and Atmospheric Sciences, Georgia Institute of Technology, Atlanta, GA, USA.
⁷ Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
⁸ Department of Molecular Medicine, the University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁹ Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.
¹⁰ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹² Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
¹³ Department of Metabolism, Digestion and Reproduction - Faculty of Medicine, Imperial College London, London, UK.
¹⁴ UK Dementia Research Institute at The University of Cambridge, Cambridge, UK.
¹⁵ Department of Clinical Neurosciences, School of Clinical Medicine, The University of Cambridge, Cambridge, UK.
¹⁶ Department of Genetics and Genomic Medicine Research & Teaching, UCL GOS Institute of Child Health, London, UK.
¹⁷ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁸ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁹ Department of Life and Environmental Sciences, University of California, Merced, Merced, CA, USA.
²⁰ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²¹ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
²² Lieber Institute for Brain Development, Baltimore, MD, USA.
²³ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁴ Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA.

^# Contributed equally.

Abstract

Evidence links air pollution to dementia, yet its role in Lewy body dementia (LBD) remains unclear. In this work, we showed in a cohort of 56.5 million individuals across the United States that fine particulate matter (PM_2.5) exposure raises LBD risk. Mechanistically, we found that PM_2.5 exposure led to brain atrophy in wild-type mice, an effect not seen in α-synuclein (αSyn)-deficient mice. 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. PM_2.5 samples from China, the United States, and Europe consistently induced proteinase-resistant αSyn strains and in vivo pathology. 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.

MeSH terms

Aged
Air Pollutants* / adverse effects
Air Pollutants* / toxicity
Air Pollution / adverse effects
Animals
Atrophy
Brain* / drug effects
Brain* / metabolism
Brain* / pathology
China
Environmental Exposure* / adverse effects
Female
Humans
Incidence
Lewy Body Disease* / chemically induced
Lewy Body Disease* / epidemiology
Lewy Body Disease* / genetics
Lewy Body Disease* / pathology
Male
Mice
Particulate Matter* / adverse effects
Particulate Matter* / toxicity
United States / epidemiology
alpha-Synuclein* / genetics
alpha-Synuclein* / metabolism

Substances

Air Pollutants
alpha-Synuclein
Particulate Matter

Abstract

MeSH terms

Substances

Grants and funding