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.

Glutathione (GSH) plays critical roles in the inflammatory response by acting as the master substrate for antioxidant enzymes and an important anti-inflammatory agent. In the early phase of the inflammatory response of macrophages, GSH content is decreased due to the down regulation of the catalytic subunit of glutamate cysteine ligase (GCLC). In the current study we investigated the underlying mechanism for this phenomenon. In human THP1-differentiated macrophages, GCLC mRNA had a half-life of 4 h under basal conditions, and it was significantly reduced to less than 2 h upon exposure to lipopolysaccharide (LPS), suggesting an increased decay of GCLC mRNA in the inflammatory response. The half-life of GCLC protein was >10 h under basal conditions, and upon LPS exposure the degradation rate of GCLC protein was significantly increased. The pan-caspase inhibitor Z-VAD-FMK but not the proteasome inhibitor MG132, prevented the down regulation of GCLC protein caused by LPS. Both caspase inhibitor Z-LEVD-FMK and siRNA of caspase-5 abrogated LPS-induced degradation of GCLC protein. In addition, supplement with γ-GC, the GCLC product, efficiently restored GSH content and suppressed the induction of NF-κB activity by LPS. In conclusion, these data suggest that GCLC down-regulation in the inflammatory response of macrophages is mediated through both increased mRNA decay and caspase-5-mediated GCLC protein degradation, and γ-GC is an efficient agent to restore GSH and regulate the inflammatory response.

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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.