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 brainon-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 diseaselike 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.

Particulate matter constituents trigger the formation of extracellular amyloid β and Tau-containing plaques and neurite shorteningin vitro

“…In addition, diesel exhaust also trigged the highest release of Aβ (blue bar in Figure 4 G), but these aggregates colocalized with neurons rather than the nanoparticles themselves (Figure 4 E; cyan color indicated colocalization of plasma membrane and Aβ signal). Furthermore, diesel exhaust particles caused massive neuronal death across the whole sample, as indicated by the presence of numerous rounded neurons with high membrane label intensity and no axons in Figure 4 E. Such effects were also observed by others in a coculture system (Block et al, 2004; Seo et al, 2023). Interestingly, in the regions where the amount of Aβ deposits was high and diesel exhaust particles colocalized with Aβ deposits, the lengths of neurites were about ten times longer compared to regions with minimal Aβ deposition.…”

Unravelling the signaling power of pollutants

“…Recent studies reported that exposure of human airway epithelial (Calu-3) cells to pollutants inhibited the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel important for mucociliary clearance (MCC) (see Glossary) [4] (Figure 2). Other studies in blood-brain barrier (BBB) models also reported that pollutants decreased protein stability of tight junctions (TJ; e.g., zonula occludens-1) and adherence junctions (E-cadherin) (Figure 3) [5]. These findings indicate that environmental pollutants can mediate decline of lung as well as brain function through elevated exacerbation frequency and increased leakage of the BBB, respectively.…”

Vascular microphysiological systems

“…Another source of neurons is neural progenitor cells that can differentiated before loading them in MPS, to study neurovascular phenotypes in Alzheimer's disease, for example [7]. Alternatively, neural progenitor cells can be differentiated on-chip, as was done in study that combined them with microglia and a cylindrical channel lined with brain endothelial cells [25 ▪ ]. The authors used this model to interrogate neuroinflammation originating from exposure to diesel exhaust particles transported through the circulatory system.…”