Anti-AD And Anti-inflammatory Effects Of QC Inhibitor LBQI-35

Alzheimer's diseases is a neurodegenerative disease that has a high incidence density with a more complex pathogenesis.It was widely focused on in the world.Impaired cognition and memory is the mainly characteristics In the clinical,at present,there is no a drug can effectively applied to clinical.and the mechanism of amyloid-?deposition(A?)is the key factor of AD,witch is widely recognized in the word.In AD's brain,there are more than 50% of amyloid-?depositions is pEA?(pGlu),witch is generated from A? cyclized by glutaminyl cyclase(QC,EC 2.3.2.5).,pEA? has stronger neurotoxicity than A?,so,finding effective inhibitions of QC enzyme activity to treat AD is a new target,and it is hoping to be a new direction of curing AD.In the early stage,the research group finished drug design according to QC protein structure,also,they finished the synthesis of the drugs and finished evaluation in vitro and got the LBQI series with high activity.Waht's more they preliminary confirmed their role resistance to AD.This paper choose LBQI – 35 whitch is one of the inhibitors as the research object,to study the effects on resistance to AD and the therapia mechanism of immune inflammation.(one)The research of resistant to ADThe research group use 2×Tg AD mous(B6C3-Tg(APPswe,PSEN1dE9)85Dbo/MmJNju)who are one month old as a model,to explore the Prevention effect on happen of AD.The results showed that LBQI-35 can effectively prevent the happening of the AD.On the basis of the research,this study used 2×Tg AD mouse.(B6C3-Tg(APPswe,PSEN1dE9)85Dbo/MmJNju)who are five months old,feed one-month LBQI-35 to explore the therapeutic effect on early alzheimer AD mice;Rerults:(1)the nesting experiment showed that compared with the control group,the treatment group socket spanner is more obvious,and the paper is more broken.In the kuang field experiment,In horizontal and vertical direction,,the treatment group were more vigorous.showed that LBQI-35 can repair thei cognitive and memory ability.(2)At the sane time,we adopted immunohistochemical staining and Thioflavin T testto test pathology of brain tissue,finded that the number of A?and pEA?Significantly reduced in the treatment group mice.(3)The GD-QC enzyme-linked test method confirmed that the activity of QC Greatly reduced.All the above results consistent with the group got before.They shows that compound LBQI-35 can inhibit QC's activity to weaken early symptoms of AD,what further provides scientific basis for the role of LBQI-35's inhibiyion on QC.(two)Rsearch on the regulation of LBQI-35 to immune inflammationImmune inflammation is an important pathological features of AD,Excessive activation of glial cells such as astrocytes and microglia will secrete a lot of immune factors,under their interact with each other,there will be feaful neuroinflammation.In the surface of A?deposition,there are plentiful immune,under their interact with each other,the neurotoxicity is exacerbate.Preliminary experiments show that LBQI-35 in AD mice model had therapeutic effect on inflammatory symptoms:(1)Immunofluorescence technique of microglia astrocytes found that compared with the control group t,the medicine group mice were drastically reduced;(2)In the Elisa experim,The contet of TNF-??IL-6?1L-1? in the theatment group had significant decrease in serum comepared with control group.It confirmed that there are serious immune inflammation in the AD;This consistent with the results of previous studies;At the same time,that proved LBQI-35 can alleviate the inflammation of AD.In order to the further exploration of LBQI – 35's regulation mechanism to the natural immune,this paper used LPS to built inflammation model with the method of intraperitoneal injection,and the the treatment group injected with LBQI – 35.Rsults show that:(1)Elisa quantitative results found that the content of TNF alpha,IL-6,CCL2 in the brain and serum was significantly increased than the blank control group.The mumber of microglia and astrocyte significantly increased in the treatment group compared with control group,this shows that inflammation model is successful.(2)The pathological indexes between control group and treated with LBQI-35 group were no significant difference.This improved that the decrease of immune factor probably because of LBQI-35'inhibition of QC,and then to lessen pEA?,as a result,lightened neurotoxicity.From what has been discussed above,LBQI-35 can be used as a QC inhibitor to inhibit enzyme activity of QC,significantly improved the pathological indicators of AD in mice.The inhibitor can inhibit enzyme activity of QC,to reduse pEA?,and then to weaken immune inflammatory cascade reaction.This study confirmed the effects of QC inhibitors LBQI-35 to resistant AD and anti-inflammatory effects.