title: NO2inhalation causes tauopathy by disturbing the insulin signaling pathway.
abstract: Air pollution has been evidenced as a risk factor for neurodegenerative tauopathies. NO2, 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 NO2-induced tauopathy. Using a dynamic inhalation treatment, we demonstrated that exposure to NO2induced 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 NO2-induced tauopathy, suggesting that the targeting of insulin signaling may be a promising therapeutic strategy to prevent this disease.
authors.affiliation: College of Environment and Resources, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: College of Environment and Resources, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Ku
authors.affiliation: College of Environment and Resources, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Yue
authors.affiliation: College of Environment and Resources, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China.
authors.forename: Guangke
authors.initials: G
authors.lastname: Li
authors.affiliation: College of Environment and Resources, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006, PR China. Electronic address: sangnan@sxu.edu.cn.
authors.forename: Nan
authors.initials: N
authors.lastname: Sang
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000397:Air Pollution; D000818:Animals; D001921:Brain / Q000473:pathology; D002490:Central Nervous System / Q000473:pathology*; D004781:Environmental Exposure; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006946:Hyperinsulinism / Q000139:chemically induced; D001239:Inhalation; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology; D009585:Nitrogen Dioxide / Q000633:toxicity*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D024801:Tauopathies / Q000139:chemically induced*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000393:Air Pollutants; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C558298:Mapt protein, mouse; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D009585:Nitrogen Dioxide
keywords: Hyperinsulinemia; Insulin resistance; Nitrogen dioxide; Synaptic protein loss; tau hyperphosphorylation