NO2 inhalation causes tauopathy by disturbing the insulin signaling pathway

Abstract

Air pollution has been evidenced as a risk factor for neurodegenerative tauopathies. NO, a primary component of air pollution, is negatively linked to neurodegenerative disorders, but its independent and direct association with tau lesion remains to be elucidated. Considering the fact that the insulin signaling pathway can be targeted by air pollutants and regulate tau function, this study focused on the role of insulin signaling in this NO-induced tauopathy. Using a dynamic inhalation treatment, we demonstrated that exposure to NO induced a disruption of insulin signaling in skeletal muscle, liver, and brain, with associated p38 MAPK and/or JNK activation. We also found that in parallel with these kinase signaling cascades, the compensatory hyperinsulinemia triggered by whole-body insulin resistance (IR) further attenuated the IRS-1/AKT/GSK-3β signaling pathway in the central nervous system, which consequently increased the phosphorylation of tau and reduced the expression of synaptic proteins that contributed to the development of the tau pathology. These findings provide new insight into the possible mechanisms involved in the etiopathogenesis of NO-induced tauopathy, suggesting that the targeting of insulin signaling may be a promising therapeutic strategy to prevent this disease.

Acute versus Chronic Exposures to Inhaled Particulate Matter and Neurocognitive Dysfunction: Pathways to Alzheimer’s Disease or a Related Dementia

“…Additionally, animal studies have demonstrated that direct NO 2 inhalation caused a worsening of spatial learning and memory and promoted dose-dependent Aβ deposition [78], while other studies have reported that direct NO 2 inhalations promote proinflammatory mechanisms that originate from the periphery, which then translocate to the brain [79][80][81], excitotoxically disrupting synaptic plasticity mechanisms of learning and memory such as long-term potentiation (LTP) [82]. Finally, NO 2 inhalations were shown to induce tauopathy by disturbing the insulin signaling pathway via p38 MAPK and/or JNK activation and IRS-1/AKT/GSK-3β attenuation [83]. Taken together, there is strong evidence that chronic exposure to high levels of anthropogenically released NO 2 in the atmosphere can lead to the genesis of neurocognitive symptoms as a function of ATN that may lead to ADRD.…”

Sulfate Aerosols Promote Lung Cancer Metastasis by Epigenetically Regulating the Epithelial-to-Mesenchymal Transition (EMT)

“…The loss of E-cad expression is an important step during the EMT developmental program in human lung cancer . Our previous study showed that exposure to PM 2.5 and PM 10 resulted in an EMT activation and extracellular matrix (ECM) degradation in A549 cells . Whereas, as a dominant composition of SIA during severe haze particulate pollution in north of China, linking these effects specifically to (NH 4 ) 2 SO 4 -exposure is somewhat difficult.…”

“…9 Our previous study showed that exposure to PM 2.5 and PM 10 resulted in an EMT activation and extracellular matrix (ECM) degradation in A549 cells. 31 Whereas, as a dominant composition of SIA during severe haze particulate pollution in north of China, linking these effects specifically to (NH 4 ) 2 SO 4 -exposure is somewhat difficult. In this study, (NH 4 ) 2 SO 4 resulted in EMT phenotype marker changes, such as a reduction in E-cad and an elevation in Fn1 in both the A549 and the BEAS-2B cell lines.…”

New Insights into Prenatal NO2 Exposure and Behavioral Abnormalities in Male Offspring: Disturbed Serotonin Metabolism and Delayed Oligodendrocyte Development

“…In the present study, considering the mice were exposed to 5 h/day, the exposure concentration of NO 2 was 1.56 ppm (TWA, based on the 8 h work shift), being in the range of reported levels in some occupational exposure places. In addition, our previous studies have demonstrated that exposure to NO 2 (2.5 ppm, 5 h/day) causes cognitive abnormalities in adult mice and male offspring but does not lead to lethality. , …”

“…In addition, our previous studies have demonstrated that exposure to NO 2 (2.5 ppm, 5 h/day) causes cognitive abnormalities in adult mice and male offspring but does not lead to lethality. 28,33 Dams in NO 2 -and air-exposed groups were sacrificed at E10.5, E13.5, E15.5, and E18.5 to obtain embryos, and the placenta and fetal brain (including forebrain and hindbrain) were dissected. Each group included at least six dams, and a total of 6−8 embryos (1, 2 embryo(s) per dam) were randomly selected for further analysis.…”