Neurotoxicity of diesel exhaust extracts in zebrafish and its implications for neurodegenerative disease

Abstract

Long-term air pollution (AP) exposure, including diesel exhaust exposure, is increasingly being recognized as a major contributor to the development of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. How AP increases the risk of neurodegeneration is not well understood but might include direct neurotoxicity and CNS inflammation. We investigated the impact of diesel exhaust particulate extract (DEPe) exposure on the brain and the mechanisms by which microglia and astroglia might mediate neuronal changes. Zebrafish (ZF) were utilized to determine neuronal toxicity of and microglial response to DEPe and single cell RNA sequencing was employed to study cell type-specific transcriptomic responses within the ZF brain. DEPe exposure induced neuronal injury and microglial activation in vivo. However, preventing the development of microglia did not attenuate DEPe-induced neuron loss, leading us to investigate microglial, astroglial, and neuronal response to DEPe exposure at single-cell resolution. Differentially expressed genes and disease-relevant pathways were identified within glial and neuronal clusters after DEPe exposure. Microglia and astroglia existed in multiple states, some of which appear toxic and others protective to neurons. Neuronal transcriptomic analysis revealed that DEPe exposure reduced expression of autophagy-related genes consistent with direct neurotoxicity. In summary, DEPe exposure was neurotoxic in developing ZF larvae and induced neuroinflammation. The microglial inflammatory response did not contribute to neurotoxicity of DEPe and in fact, some glial clusters upregulated transcriptional pathways that are likely protective. Furthermore, DEPe exposure led to reduced expression of autophagy-related genes in neurons that likely contribute to its toxicity.

Stat3 mediates Fyn kinase driven dopaminergic neurodegeneration and microglia activation

“…The top 50 genes with highest changes in gene expression in 5 dpf vs. 3 dpf elavl3:Gal4; UAS:fynY531F larva included serine proteases prss1 and prss59.1, and cathepsins ctsbb and ctsl, which are involved in proteolysis and metabolism in cytokine-related neuroinflammation (Ha et al 2022;Jiang et al 2022). Top genes in 5 dpf elavl3:Gal4; UAS:fynY531F vs. control elavl3:Gal4 included the ortholog of activated macrophage gene acod1/irg1 immune responsive gene irg1l and the Stat3 target timp4.1 (Fig.…”