Diesel exhaust particles disrupt mouse and human iPSC-derived microglial function and Amyloid-β clearance in Alzheimer’s disease models

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, yet the environmental drivers that accelerate its progression remain poorly defined. Traffic-related air pollution is emerging as a modifiable AD risk factor, but how inhaled particles perturb microglial clearance of amyloid beta (Aβ) is unknown. Microglia are the principal Aβ-clearing phagocytes of the brain. Here, we showed that exposure of primary mouse microglia and human induced pluripotent stem cell-derived microglia (iMGLs) to 3–100 µg/mL diesel exhaust particles (DEP) disrupted microglial homeostasis, induced morphological abnormalities, increased reactive oxygen species, impaired lysosomal degradation, and led to a concentration-dependent loss of phagocytic capacity. Importantly, DEP markedly reduces Aβ uptake in both species. Transcriptomic profiling revealed a DEP-induced, non-canonical state characterized by metabolic reprogramming, broad suppression of inflammatory pathways, antigen-presentation, chemokine, and species-specific remodeling during subsequent Aβ challenge, including defective chemotaxis, cell cycle, and cytoskeletal signatures. These data show that DEP profoundly alters microglial transcriptional and metabolic states, leading to impaired Aβ clearance, which could, thereby, further contribute to AD progression.