The Effect And Molecular Mechanism Of PM_2.5 Exposure On Neurodegenative Tau Lesion

Due to the rapid increase in the global population and the acceleration of urbanization,emissions of atmospheric pollutants are increasing.Compared with other pollutants,fine particulate matter(PM_2.5)has a stronger pathogenic and lethal effect because of its complex composition,special physical and chemical properties.Many evidences have pointed out that the harzadous effect of PM_2.5 exposure is not limited to the respiratory system damage,but also covers the central nervous system?CNS?,heart,and endocrine system.PM_2.5 is regarded as the best indicator to evaluate air pollution-related health risks,and its pollution effects have become a major issue to be urgently addressed in the global environmental field.With a small size,PM_2.5 is easy to be deposited in the respiratory tract and transferred to other potential targeting organs outside the lungs,including the CNS.Recently,researches on PM_2.5-related air pollutants induced tauopathy have emerged gradually,but researches on its mechanism are still lacking.In view of the situation,our study is proposed to explore the neurodegenerative tau lesion induced by PM_2.5 exposure in mice and its underlying mechanism.In this study,a PM_2.5 exposure model was established.Adult male C57BL/6 mice were exposed by oropharyngeal aspiration every other day for4 weeks.The animals of exposure group were treated with 5 mg/kg bw PM_2.5,the control group was given saline solution.After exposure,water maze was used to test the effects of PM_2.5 exposure on spatial learning and memory.Western Blot was used to detect the level of phosphorylation of tau in mice brain,insulin signaling pathway-related factors?insulin receptor substrate-1?IRS-1?and protein kinase B?AKT??,and phosphorylating kinase of tau?glycogen synthase kinase-3?,GSK-3??.Enzyme-linked immunosorbent assay?ELISA?was used to measure fasting serum insulin levels.The results have shown that PM_2.5 exposure led to excessive phosphorylation of tau in mice,and then caused neurodegenerative tau injury,reduced the number of times crossing platform in the water maze.Exposure to PM_2.5 also inducedlow expression of IRS-1/AKT and P-GSK-3?,which is the reason for the large accumulation of phosphorylated tau?P-tau?.At the same time,PM_2.5inhalation also caused systemic insulin resistance?IR?in mice,which triggers compensatory high serum insulin expression.Our previous study has confirmed that PM_2.5 exposure caused tau lesion by disturbing insulin signaling pathway.PM_2.5-related CNS damage begins in utero,for learning whether indirect exposure to PM_2.5 causes offspring's tau lesion,a PM_2.5 maternal exposure model was established in this study.The C57BL/6 pregnant mice were exposed by oropharyngeal aspiration every other day during the whole pregnancy,PM_2.5-treated group mice were treated with 3 mg/kg bw PM_2.5 and the control group was given a saline solution with blank filter membranes.Water maze test was performed at postnatal day 21?PND21?to detect effect of PM_2.5 maternal exposure on the spatial learning and memory ability of male offspring.Male offspring were sacrificed on PND1,PND7,and PND21.The hippocampus of PND1 mice was extracted for observing PSD-95 by transmission electron microscope.Then immunofluorescence staining and Western Blot were used to detect the expression of P-tau;Western Blot and ELISA were used to examine the levels of insulin-related factors;and real-time quantitative RT-PCR was used to detect the level of synaptic transmission-related factors.The results have shown that,maternal PM_2.5 exposure disturbed insulin signaling pathway of male offspring,leading to the accumulation of P-tau and tau protein damage,which resulted in abnormal synaptic transmission function and decline of spatial learning and memory ability.Meanwhile,systemic IR caused by PM_2.5exposure still promoted high serum insulin expression in male offspring.However,these pathological changes would recover gradually with the later growth of male offspring.In this study,models of PM_2.5 exposure and maternal PM_2.5 exposure were established,revealing that PM_2.5 exposure is related to the occurrence of tau lesion,which was mediated by PM_2.5-induced insulin signaling disorder.This study showed new ideas for prevention and diagnosis of similar diseases,and provided experimental evidence for the health effects study of air pollutants.