大気汚染とレビー小体型認知症リスクの分子機構を解明(Potential Molecular Link Between Air Pollutants and Increased Risk of Lewy Body Dementia Revealed)

2025-09-03 コロンビア大学

<関連情報>

• https://www.publichealth.columbia.edu/news/potential-molecular-link-between-air-pollutants-increased-risk-lewy-body-dementia-revealed
• https://www.science.org/doi/10.1126/science.adu4132

大気汚染物質によるレビー小体型認知症の促進 Lewy body dementia promotion by air pollutants

Xiaodi Zhang, Haiqing Liu, Xiao Wu, Longgang Jia, […] , and Xiaobo Mao
Science  Published:4 Sep 2025
DOI:https://doi.org/10.1126/science.adu4132

Editor’s summary

Air pollution was recently found to be associated with increased risk of developing dementia. Zhang et al. investigated the relationship between PM_2.5, an index of particle pollution, and the development of Lewy body dementia (LBD), the second most common form of dementia. Epidemiological data showed that PM_2.5 exposure was associated with an increased risk of developing LBD. In mice, nasal administration of PM_2.5 led to brain atrophy due to the accumulation of pathological α-synuclein, loss of dopaminergic neurons in the substantia nigra, and impaired cognition and motor function. The results identify a potential mechanistic link between air pollution and the development of dementia. —Mattia Maroso

Structured Abstract

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 PM_2.5 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 (PM_2.5), could trigger initial αSyn misfolding and propagation into the brain. However, epidemiological relationships between PM_2.5 exposure and LBD versus PD subtypes lacked large-scale substantiation. Whether PM_2.5 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 PM_2.5-LBD link.

First, analysis of >56 million US Medicare beneficiaries revealed that chronic PM_2.5 exposure was significantly associated with first hospitalizations for α-synucleinopathies. A key finding was that the link between PM_2.5 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 PM_2.5-related neurological disorders. 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.

Third, we found that PM_2.5 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 PM_2.5 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 PM_2.5 exposure to LBD. The neurotoxic effects of PM_2.5 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 PM_2.5-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.

PM_2.5 promotes LBD by inducing a distinct αSyn strain.
(A) PM_2.5 exposure is associated with a higher relative risk of LBD compared to PD without dementia. (B) Chronic PM_2.5 exposure leads to brain atrophy in WT mice, an effect abolished in αSyn-knockout (αSyn^–/–) mice. (C) Mechanistically, PM_2.5 triggers an LBD-like αSyn strain and elicits a corresponding transcriptomic profile characteristic of LBD pathology.

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.