PM2.5 Exacerbate Cognitive Impairment In Mice Model With Alzheimer’s Disease By Affects Synapses,Mitochondrial Function

Background Alzheimer’s disease(AD)is a neurodegenerative disease that deteriorates over time.AD patients are characterized by progressive memory decline,spatial localization disorder,personality and behavior changes,etc.There are many pathogenesis mechanisms of AD,among which the role of exposed to air pollutants in the environment,especially fine particulate matter(PM2.5),in the etiology of AD has attracted much attention in recent years.However;the mechanism of congtive impairment caused by PM2.5 is not yet clear,and it is not clear whether the high concentration of PM2.5 exposure leads to the early occurrence or aggravation of cognitive impairment in AD.Therefore,this project intends to establish a mice model of PM2.5 exposure,explore the relationship between high-concentration PM2.5 exposure and cognitive impairment,and explore the mechanism,in order to supply early warning to the risk of exposure to high concentration PM2.5,and supply further clews to the prophulaxis and treatment of cognitive disorders such as AD.Methods Firstly,the PM2.5 exposure system was constructed.The 8-week-old Alzheimer’s disease model mice(APP/PS1)and C57BL/J control mice was exposed to PM2.5 for 15 weeks.The effects of fine particulate matter(PM2.5)on the cognitive function,neuropathology and other aspects of AD model mice were discussed from the holistic perspectives,and the correlation between the pathological changes and PM2.5 was analyzed.Experimental animals were divided into AD model mouse exposure group(ePAP)and AD model mouse control group,C57 exposure group(eC57)and control group,with 9 animals in each group.The experimental group was exposed to high concentration of fine air particulate matter in the enrichment chamber for 4h/d and 5d/week for 15 weeks,and the control group was under the filtered air.After the exposure,behavioral experiments were carried out immediately to explore the effect of PM2.5 exposure on the behavior of mice.After the behavioral experiment,the PET-CT experiment was conducted to detect the cerebral glucose metabolism rate.Then we adopted blood analysis and biochemical method to detect the liver and renal function and evaluate the lipid metabolism in model mice.After that,cardiac perfusion fixed anatomy was performed to take brain,lung,heart,liver,kidney,gastrointestinal and other organs for histopathological and molecular biology tests,including:evaluation of brain,kidney and liver histopathology with HE staining;The immunohistochemistry was used to detected Aβ and Iba1 in the cerebral cortex and hippocampus.The level of inflammatory cytokines in brain tissue was measured by liquid suspension microarray.Transmission Electron Microscope(TEM)was used to observe the ultrastructure changes of hippocampal and cortical tissues,synapses and mitochondria in mice.We adopted Western Blot to test the expression levels of synaptic proteins NR2B,PSD-95and p-CREB,as well as mitochondrial clease-related proteins DRP1,MID49 and MID51.In addition,we used 16S rRNA high-throughput sequencing to explore the differences in intestinal microecology composition of mice in each group,so as to analyze the impact of PM2.5 exposure on intestinal flora.Results The results of the exposure experiment showed that high concentration of PM2.5 exposure could cause pathological changes in the lung ti ssues of mice,and the mice model of PM2.5 exposure was successfully established.In the exposed group,the mice showed cognitive dysfunction,impaired working memory ability,significantly increased anxiety,and no significant decline in spatial memory ability.In terms of pathology,no obvious organ pathological damage was observed in the exposed group except the lungs,and the Aβ plaque was significantly increased in the ePAP group.The markers of microglia-Ibal,were significantly increased,accompanied by the increased inflammatory factors in the brain.The WB results showed that several proteins related to learning and memory were changed to different degrees,and the expressions of mitochondrial related proteins,DRP1 and MID51 were increased in the exposed group.The PET-CT results showed that glucose metabolism rate decreased in eC57 group compared with the control group.In terms of the ultrastructure of the exposed group and the control group,it was found that the mitochondria of the exposed group were significantly damaged under the electron microscope,and a large number of mitochondrial vacuolation,and the cristae structure disappeared,accompanied by the increase of Aβ plaque.In this study,The detection results of intestinal flora showed that chronic PM2.5 exposure could damage the structure of intestinal flora in mice,induce the imbalance of Firmicutes/Bacteroidetes and impair the normal physiological function of the intestinal tract.Conclusion In this study,it was found that high concentration of PM2.5 exposure significantly increased the anxiety state of AD model mice and C57 mice.Exposure to high concentration PM2.5 can induce cognitive dysfunction and impaired.working memory in mice,and at the same time,it has the characteristics of aggravating AD like pathological features(Aβ plaque,increased neuron necrosis,and increased inflammatory response).It is an experimental animal model that can well simulate cognitive impairment caused by human haze inhalation.High concentration of PM2.5 may damage the nervous system by increasing the deposition of amyloid plaques in the brain,inflammatory response and disruption of mitochondrial morphology and function.It can destroy the structure of gut flora.Maintaining intestinal flora balance may be the entry point to slow down the progression of AD.