The Experssion And Mechanism Of Chitinase1 In Models Of Alzheimer’s Disease

PART ONE: THE EXPRESSION OF CHITINASE1 IN AGED APP/PS1 TRANSGENIC MICEAim: It is reported that CHIT1 increases in AD.However,the alteration of CHIT1 in the progress of AD is still unclear.Thus,the present study detect CHIT1 level in 22 months-old APP/PS1 double transgenic mice,and combined with primary results of our team to investigate the possible relationship between AD and CHIT1.Methods: Experimental models were APP/PS1 double transgenic mice with 22 months,and the controls were the same age wild type mice.Cognitive function was detected by Morris water maze test in APP/PS1 mice as well as controls.ELISA and the q RT-PCR were used to detect CHIT1 level in brain tissues of mice.Results: CHIT1 increased significantly in APP/PS1 mice aged 22 months compared with the age matched wild-type group by ELISA and q RT-PCR,and Morris water maze showed that 22 months-old APP/PS1 mice prolong the escape latency and significantly shorten the percentage of target quadrant time-consuming.Conclusions: The spatial learning and spatial memory in 22 months-old APP/PS1 mice are declined with the increasing level of CHIT1.Combining with previous experimental results of our team in 4 months-old and 12 months-old APP/PS1 mice,cognitive impairment is not prominent in early stage of AD(4 months-old APP/PS1 mice),while the moderate and severe of AD in APP/PS1(12 months-old and 22 months-old APP/PS1 mice)shows the significant cognition disorder.Time-dependent increase of CHIT1 in APP/PS1 double transgenic mice indicates that the level of CHIT1 is associated with decline of cognition.Therefore,CHIT1 might be a biomarker of disease progression in AD.PART TWO: THE MECHANISM OF CHITINASE1 IN ALZHEIMER’S DISEASE MODELS INDUCED BY D-GALACTOSE AND ALCL3Aim: CHIT1 activity is increased in AD.However,the role of CHIT1 in AD is unknown.We investigated the effects of CHIT1 on Alzheimer’s pathology and microglia function.Methods: Artificial CHIT1 and CHIT1 inhibitor(chitinase-IN-2)were used to determine the effects of CHIT1 on inflammatory factors and β-amyloid(Aβ)oligomers deposition in D-galactose and Al Cl3 induced AD model in rats.Cognitive functioning in the rats was assessed using the Morris Water Maze.Aβ-treated N9 microglia cells were analyzed to further verify whether the changes in inflammatory factors following CHIT1 treatment were associated with microglia alternative activation.Results: Our data displayed that the activity of CHIT1 was both improved in D-galactose and Al Cl3 injected rats and Aβ pretreated microglia.Moreover,there was an improvement in cognitive function in CHIT1 treated AD rats.Furthermore,anti-inflammation factors(Arginase 1,Arg-1,mannose receptor type C 1,MRC1/CD206)were increased and pro-inflammation factors(tumor necrosis factor alpha,TNF α,interleukin 1 beta,IL-1β)were decreased in D-galactose/Al Cl3 induced AD rats with CHIT1 treatment.A higher level of M2 markers(Arg-1,MRC1/CD206)and a lower level of classic M1 markers(TNFa,IL-1β)were obtained in Aβ pretreated N9 cells with CHIT1,suggesting that CHIT1 polarized the microglia into an anti-AD M2 phenotype.We also detected that CHIT1 could weaken the deposition of Aβ oligomers in the brain of D-galactose and Al Cl3 induce AD rats.Conclusion: CHIT1 might exert protective effects against AD by polarizing microglia to an M2 phenotype and resisting Aβ oligomers deposition.