Chandelier
Senior Member (Voting Rights)
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, AND XIAOBO MAO
Editor’s summary
Air pollution was recently found to be associated with increased risk of developing dementia. Zhang et al. investigated the relationship between PM2.5, an index of particle pollution, and the development of Lewy body dementia (LBD), the second most common form of dementia. Epidemiological data showed that PM2.5 exposure was associated with an increased risk of developing LBD. In mice, nasal administration of PM2.5 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 MarosoStructured 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 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.
