Neurotoxicity of Diesel Exhaust Particles

Article type: Research Article

Authors: Shkirkova, Kristina^a | Lamorie-Foote, Krista^a | Zhang, Nathan^b | Li, Andrew^b | Diaz, Arnold^c | Liu, Qinghai^a | Thorwald, Max A.^c | Godoy-Lugo, Jose A.^c | Ge, Brandon^a | D’Agostino, Carla^c | Zhang, Zijiao^d | Mack, Wendy J.^a | Sioutas, Constantinos^d | Finch, Caleb E.^{b; c} | Mack, William J.^a | Zhang, Hongqiao^{c; *}

Affiliations: [a] Keck School of Medicine, University of Southern California, Los Angeles, CA, USA | [b] Dornsife College, University of Southern California, Los Angeles, CA, USA | [c] Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA | [d] Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Hongqiao Zhang, PhD, Assistant Professor, School of Gerontology, University of Southern California, 3715 McClintock Ave. GER313, Los Angeles, CA 90089, USA. Tel.: +626 272 7968; E-mail: [email protected].

Abstract: Background:Air pollution particulate matter (PM) is strongly associated with risks of accelerated cognitive decline, dementia and Alzheimer’s disease. Ambient PM batches have variable neurotoxicity by collection site and season, which limits replicability of findings within and between research groups for analysis of mechanisms and interventions. Diesel exhaust particles (DEP) offer a replicable model that we define in further detail. Objective:Define dose- and time course neurotoxic responses of mice to DEP from the National Institute of Science and Technology (NIST) for neurotoxic responses shared by DEP and ambient PM. Methods:For dose-response, adult C57BL/6 male mice were exposed to 0, 25, 50, and 100μg/m3 of re-aerosolized DEP (NIST SRM 2975) for 5 h. Then, mice were exposed to 100μg/m3 DEP for 5, 100, and 200 h and assayed for amyloid-β peptides, inflammation, oxidative damage, and microglial activity and morphology. Results:DEP exposure at 100μg/m3 for 5 h, but not lower doses, caused oxidative damage, complement and microglia activation in cerebral cortex and corpus callosum. Longer DEP exposure for 8 weeks/200 h caused further oxidative damage, increased soluble Aβ, white matter injury, and microglial soma enlargement that differed by cortical layer. Conclusion:Exposure to 100μg/m3 DEP NIST SRM 2975 caused robust neurotoxic responses that are shared with prior studies using DEP or ambient PM0.2. DEP provides a replicable model to study neurotoxic mechanisms of ambient PM and interventions relevant to cognitive decline and dementia.

Keywords: Air pollution, Alzheimer’s disease, brain, dementia, diesel exhaust particle, neurotoxicity

DOI: 10.3233/JAD-220493

Journal: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1263-1278, 2022