Lewy body dementia promotion by air pollutants

Evidence links air pollution to dementia, yet its role in Lewy body dementia (LBD) remains unclear. Here we show in a cohort of 56.5 million individuals across the U.S. that PM2.5 exposure significantly raises LBD risk. Mechanistically, we find PM2.5 exposure leads to brain atrophy in wild-type mice, an effect not seen in a-synuclein (aSyn)-deficient mice. PM2.5 exposure generates a highly pathogenic aSyn strain, PM-PFF, with enhanced proteinase K-resistance and neurotoxicity, resembling aSyn LBD strains. PM2.5 samples from China, the U.S., and Europe consistently induce proteinase-resistant aSyn strains and in vivo pathology. Transcriptomic analyses reveal shared responses between PM2.5-exposed mice and LBD patients, underscoring PM2.5's role in LBD and the stresses the need for interventions to reduce air pollution and its associated neurological disease burden. Overall design: 2-month-old humanized WT aSyn mice (FVB; 129S6-Sncatm1Nbm Tg (SNCA)1Nbm/J, Strain: 010710), obtained from The Jackson Laboratory (Bar Harbor, ME, USA), were used for RNA sequencing experiments. The mice were divided into five groups: the PBS group (intranasal administration of PBS), the PM2.5 group (intranasal administration of PM2.5), the PFF group (PFF injection), the PM-PFF group (PM-PFF injection), and the PM-PFF with PM2.5 exposure group (PM-PFF injection followed by intranasal PM2.5 administration one week later). All treatments were administered for a duration of 2 months.