Neuro‐Glia‐Vascular‐on‐a‐Chip System to Assess Aggravated Neurodegeneration via Brain Endothelial Cells upon Exposure to Diesel Exhaust Particles

Abstract Air pollution induces neurodegeneration, including cognitive deficits, neuroinflammation, and disruption of the blood–brain barrier. The mechanisms underlying air pollution‐mediated neurodegeneration have not yet been fully elucidated given the limited knowledge on intercellular interactions. A brain‐on‐a‐chip platform is presented comprising neurons, glia, and brain endothelial cells (bECs; neuro‐glia‐vascular, NGV) and diesel exhaust particle (DEP)‐induced neurodegeneration is evaluated with a particular focus on the intercellular interactions. DEP exposure in the NGV model yields Alzheimer's disease‐like signatures, including amyloid beta accumulation, tau phosphorylation, hydrogen peroxide (H 2 O 2 )/reactive oxygen species (ROS) production, and neuronal cell death. bEC‐secreted granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) stimulates microglial activation and the overproduction of H 2 O 2 /ROS in microglia, suggesting that the bEC‐microglia‐neuron is a neurodegeneration cascade. Pharmacological inhibition at each step of the cascade, including GM‐CSF neutralization, microglial activation suppression, and ROS scavenging, prohibits neurodegeneration in the NGV model. Therefore, intercellular interactions should be further studied of air pollution‐induced neurodegeneration.