PM_2.5 And Formaldehyde Exposure Induce Alzheimer-like Lesions In Mouse Brain And Its Molecular Mechanism

With an aging population that continues to grow,Alzheimer's disease(AD)has resulted in heavy burdens for more and more elders and their families.As a typical neurodegenerative disease,AD has become a severe social and medical problem.Though the specific genes related to AD have been identified,the genetic factors fail to fully account for the pathogenesis of AD.Therefore,the roles of environment and life styles in the occurrence of AD are being actively probed.Based on the above-mentioned reasons,I chose air pollutants,i.e.PM2.5 and formaldehyde(FA),as subjects of this research.According to the extant epidemiological researches,exposures to PM2.5 and FA bear certain relevance to the occurrence of AD.But there are still few researches on these exposures,especially on the in-vivo and molecular mechanisms of co-exposure for the AD-like lesions of brain tissues.Therefore,the Thesis copes with the influence from exposures to PM2.5 and FA(the sole exposure to PM2.5/the sole exposure to FA/co-exposure to PM2.5 and FA)on the AD-like lesion of mouse brain tissues,in order to present favorable evidence for researches on the relationship between AD and exposures to PM2.5 and FA.The Thesis consists of five chapters:In Chapter ?:I introduced the status quo of global population aging and AD,and the main hypotheses on the pathogenesis of AD;analyzed the influence on central nervous system and AD from air pollution,PM2.5 pollution and FA pollution;and at last described the context for my topic selection and the content of the Thesis.In Chapter ?:With the subject of PM2.5,I investigated the influence from the sole exposure to PM2.5 on AD-like lesions of mice and its possible molecular mechanism.By exposing mice to PM2 5 by intranasal instillation for 7 days,we found that exposure to PM2.5 at a certain concentration might result in decreased cognitive competence,pathological damage to brain tissues,and increased expression of amyloid-? protein and phosphorylated Tau protein,which were typical AD pathological symptoms.By measuring the oxidative stress molecular pathway related indicators(ROS,MDA,GSH,SOD,8-OHdG,NF-?B,TNF-?,IL-1?,COX-2,glial cell activation).We found that oxidative stress is one of the molecular mechanisms of AD-like lesions after PM2.5 exposure.The low exposure dose(environmental exposure)-0.193 mg/Kg/day(equivalent to 100 ?g/m3 for human)-was relatively safe in an exposure period of 7 consecutive days.In Chapter III:With the subject of FA,I discussed the influence from the sole exposure to FA on AD-like lesion of mice and its possible molecular mechanism.By exposing mice to FA by intranasal instillation for 7 days,we found that exposure to FA at high concentration might result in typical AD pathological symptoms and that oxidative stress is one of the molecular mechanisms of AD-like lesions after exposure to FA.The low exposure dose(environmental exposure)-0.155 mg/Kg/day(equivalent to 0.08 mg/m3 for human)-was relatively safe in al exposUre period of 7 consecutive days.In Chapter IV:Based on the findings of Chapter II and III,I co-exposed mice to PM2.5at 0.193 mg/Kg/day and FA at 0.155 mg/Kg/day for 7 consecutive days,to probe whether the two seeming safe exposure concentrations would still be safe under co-exposure.It was showed that:the safe concentration,which failed to cause AD-like lesions of the mice under the sole exposure,resulted in damage to the mouse brain tissues and AD-like lesions under the co-exposure,and oxidative stress had played an important role in AD-like lesions after co-exposure.The findings of this chapter indicated that the relatively safe concentration for the sole exposure turned out to be unsafe for co-exposure.Since environmental pollution is a complicated co-exposure system,considering the function and effect of co-exposure,the safety standards of each pollutant may be made even stricter,which also provided a reference for the later formulation of safe dose or safety standards of pollutants..In Chapter V:Based on the findings of the above chapters,an additional group of Vit E protective agent was applied,in the similar approaches with those of the above chapters,to further testify the role of oxidative stress in AD-like lesions caused by exposures to PM2.5 and FA.It indicated that when the Vit E was added,the oxidative stress level of the mouse brain tissues decreased and the AD-like lesions caused by co-exposure to PM2.5 and FA was moderated.This further demonstrated the role of oxidative stress in AD-like lesions caused by exposures to PM2.5 and FA,and meanwhile provided some implications for how to moderate the damage from exposures to PM2.5 and FA.