The microtubule-associated tau protein forms pathological inclusions that accumulate in an age-dependent manner in tauopathies including Alzheimer's disease (AD). Since age is the major risk factor for AD, we examined endogenous tau species that evolve during aging in physiological and diseased conditions. In aged mouse brain, we found tau-immunoreactive clusters embedded within structures that are reminiscent of periodic acid-Schiff (PAS) granules. We showed that PAS granules harbor distinct tau species that are more prominent in 3xTg-AD mice. Epitope profiling revealed hypo-phosphorylated rather than hyper-phosphorylated tau commonly observed in tauopathies. High-resolution imaging and 3D reconstruction suggest a link between tau clusters, reactive astrocytes, and microglia, indicating that early tau accumulation may promote neuroinflammation during aging. Using postmortem human brain, we identified tau as a component of corpora amylacea (CA), age-related structures that are functionally analogous to PAS granules. Overall, our study supports neuroimmune dysfunction as a precipitating event in tau pathogenesis.

Air pollution has become the world’s single biggest environmental health risk of the past decade, causing millions of yearly deaths worldwide. One of the dominant air pollutants is fine particulate matter (PM2.5), which is a product of combustion. Exposure to PM2.5 has been associated with decreased lung function, impaired immunity, and exacerbations of lung disease. Accumulating evidence suggests that many of the adverse health effects of PM2.5 exposure are associated with lung inflammation and oxidative stress. While the physical structure and surface chemistry of PM2.5 are surrogate measures of particle oxidative potential, little is known about their contributions to negative health effects. In this study, we used functionalized carbon black particles as surrogates for atmospherically aged combustion-formed soot to assess the effects of PM2.5 surface chemistry in lung cells. We exposed the BEAS-2B lung epithelial cell line to different soot at a range of concentrations and assessed cell viability, inflammation, and oxidative stress. Our results indicate that exposure to soot with varying particle surface composition results in differential cell viability rates, the expression of pro-inflammatory and oxidative stress genes, and protein carbonylation. We conclude that particle surface chemistry, specifically oxygen content, in soot modulates lung cell inflammatory and oxidative stress responses.

In the past 50 years, the number of publications on air pollution and lung disease has increased considerably, although the number of studies considering sex (a biologic factor), or gender (a social construct), has remained low and stagnant. Accumulating data from studies assessing the effects of the environment on lung health have shown direct associations of air pollution exposures with lung inflammation. Sex-specific disaggregation of data has indicated that substantialbut frequently overlookeddifferences exist between men and women, highlighting the importance of sex-and gender-stratified analyses to guide the deployment of safe and effective therapeutics options for males and females. In this chapter, we present an overview of the scientific evidence on differential effects of environmental exposures in men and women. We summarize clinical studies and research using animal models aiming to elucidate sex-specific mechanisms of inflammation and toxicity from a wide range of air pollutants. Understanding these mechanisms can lead to the development of more personalized prevention efforts and better-informed environmental policies accounting for sex, gender, and hormonal status.

Air pollution has become the world’s single biggest environmental health risk of the past decade, causing about 7 million yearly deaths worldwide. One of the dominant air pollutants is fine particulate matter (PM2.5), a product of combustion. Exposure to PM2.5 has been associated with decreased lung function, impaired immunity, and exacerbations of lung disease. Accumulating evidence suggests that many of the adverse health effects of PM2.5 exposure are associated with lung inflammation and oxidative stress. While the physical structure and surface chemistry of PM2.5 are surrogate measures of particle oxidative potential, little is known about their contributions to negative health effects. In this study, we used functionalized carbon black particles as surrogates for atmospherically aged combustion formed soot to assess the effects of PM2.5 surface chemistry in lung cells. We exposed the BEAS-2B lung epithelial cell line to different soot at a range of concentrations, and assessed cell viability, inflammation, and oxidative stress. Our results indicate that exposure to soot with varying particle surface composition results in differential cell viability rates, expression of pro-inflammatory and oxidative stress genes, and protein carbonylation. We conclude that particle surface chemistry, specifically oxygen content, in soot modulates lung cell inflammatory and oxidative stress responses.

Objective Air pollution is a lasting global health hazard which has a serious toxicological effects on human health. Long and short term exposure to air pollutants has been associated with respiratory and cardiovascular diseases, skin diseases, and long‐term chronic diseases such as cancer and asthma. Although air pollution is produced by a variety of sources, one of the major air pollutants is fine particulate matter ranging mostly from 2.5 to 10 μm (PM2.5 to PM10). Carbon black, produced by incomplete combustion of heavy petroleum products (soot), comprises a significant portion of PM. Growing evidence suggests that many of the adverse health effects of PM are associated with oxidative stress and inflammatory responses. This work focuses on the identification of oxidative and pro‐inflammatory factors induced by exposure of human lung epithelial cells to combustion‐produced soot in various surface chemistry forms. Methods A lung epithelial cell line (BEAS‐2B) was exposed to lab‐generated R‐250 carbon black (nascent, nitric acid‐treated, and ozone‐treated carbon) for 6hr and 24hr incubation times, at different concentrations (0–100 ug/mL). Cell viability was measured using the MultiTox‐Fluor Multiplex Assay. RNA and protein were extracted from cells to evaluate expression of inflammatory cytokines (IL‐1b, IL‐6) and genes related to the inflammatory response and oxidative stress (SOD2, NFE2L2, HO‐1, and CCL2) by real time polymerase chain reaction (PCR). The expression of protein oxidation products (carbonylated proteins) was measured using ELISA Protein Carbonyl Kit. Cell apoptosis was measured by western blot detection of cleaved Caspase‐3. Results Cell viability was decreased with increasing PM2.5 treatment concentrations at both time points. Nitric acid‐treated carbon resulted in the largest decrease in cell viability. Nitric acid and ozone‐treated particles resulted in increased protein carbonylation when compared to the nascent particles, indicating oxidative stress. Protein carbonylation significantly increased from 6hr to 24hr PM2.5 exposure, particularly for the nitric acid‐treated particles. Gene expression of the inflammatory cytokines IL‐1b, and IL‐6 was upregulated with increasing concentrations of PM2.5 exposure (1.56–50 ug/mL), particularly for nitric acid‐treated particles. An increase in gene expression was observed for oxidative stress markers CCL2, SOD2, NFE2L2 and HO‐1 higher concentrations of PM2.5 exposure (1.56–12.5 ug/mL). Conclusion Exposure of PM2.5 to human lung epithelial cells decrease cell viability and increases inflammatory responses and oxidative stress. PM2.5 surface functional groups strongly influence the extent of toxicity, and future experiments will focus on how functional groups affect cell viability and the observed inflammatory responses of human lung epithelial cells. Support or Funding Information This work was supported by startup funds from The University of North Carolina at Chapel Hill and Penn State College of Medicine (PS), and the Penn State University Human Healt...