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.

BackgroundExposure to urban air pollution particles is strongly associated with higher risks of accelerated cognitive decline, cerebral atrophy, and dementia in multiple population studies. Among possible mechanisms is the decrease of neurotrophins, shown for BDNF in human exposures, which have critical roles in regulating adult neurogenesis and synaptic plasticity.MethodC57BL/6 mice were exposed to nano‐sized particulate matter (nPM, batch nPM2016a) from urban traffic air pollution for 8 weeks and the mRNAs of neurotrophins and receptors in mouse brain were measured by qPCR assay and neural stem cells measured by immunohistochemistry.ResultnPM exposure altered mRNA levels of neurotrophin genes (Ngf, Bdnf, Ntf‐3 and Ntf‐4/5) with brain region‐specificity. In cerebral cortex (CX), Ngf and Ntf‐3 were decreased (17% and 29% respectively), Ntf‐4/5 increased (78%), and Bdnf unchanged. In hippocampus (HP), Bdnf and Ntf‐4/5 were decreased (40% and 38% respectively) while Ngf and NTF‐3 unchanged. In olfactory bulb (OB), only Bdnf was decreased (10%). The mRNAs of neurotrophin receptors (Trka, Trkb, Trkc and p75Ntr) in CX, HP and OB were less responsive to nPM exposure, and only shown by OB with 22% decrease of p75Ntr and 14% decrease of Vgr (VGF nerve growth factor inducible). Exposure to nPM increased the quiescence of neural stem cells in hippocampal SGZ by IHC assay (Control 69.3% VS nPM 76.6%, P = 0.02), but did not alter the total number of neural stem cells. .ConclusionChronic air pollution exposure altered neurotrophin signaling with factor‐ and brain region‐specificity, and increased neural stem cell quiescence.