Anti-AD Effect Of QC Inhibitor And Chinese Herbal Extracts

Alzheimer disease(AD)has become a worldwide health,economic and social problem.Due to the unclear pathogenesis,there is no clinically anti-AD drug in the clinic.Recent studies have found that glutaminyl cyclase(QC)can induce AD by catalyzing the production of N-terminal pyroglutamate(p E)virulence factors,and its expression level and activity are positive with the development of AD.Therefore,the inhibition of QC activity is expected to become a new direction for the development of anti-AD drugs.In the previous study,it has carried out a series of exploratory research work on the research of QC anti-AD lead drugs,and made positive progress.This article further broadens the research level of QC inhibitor anti-AD mechanism to better reveal its anti-AD mechanism;and attempts to discover new QC-targeted anti-AD active substances,providing research support for antiAD drug development.To this end,the main contents and results of this study include:1.Study on the mechanism of anti-AD action of QC inhibitor DPCI-23.DPCI-23 was selected as a representative compound in the previous study of the research group.The doubletransgenic AD mouse(APP/PS1)was used as a model to systematically study the anti-AD mechanism of QC inhibitors.(1)This study used behavioral experimental techniques such as water maze to study the differences in learning,memory,and spatial exploration of AD mice in each group.The results showed that mice in the drug-administered group were compared with the blank control mice.(2)Using GD-QC enzyme-linked method,WB and other methods to study the inhibitory effect of DPCI-23 on mouse brain QC,the results showed that the compound has a good inhibitory effect on QC,and it can significantly inhibit the formation of p E-Aβ in the brain and the formation of total Aβ plaques.(3)The supernatant of mouse hemibrain,kidney and liver homogenate,serum IL-6 and TNF-α were detected by ELISA methods.The levels of IL-1β and IFN-γ showed that the levels of each factor in the mice in the drugadministered group were lower than those in the control group,indicating that DPCI-23 had a certain alleviating effect on inflammation in vivo.The above experiments show that DPCI-23 can reduce the production of p E-Aβ by inhibiting QC activity,reduce the neuroinflammatory reaction in the brain,and achieve anti-AD effect.2.Exploratory discovery studies targeting QC natural anti-AD active substances.In order to broaden the discovery channels of anti-AD active substances,this study selected some Chinese medicines to study the inhibitory activity of extracts on QC.(1)Using GD-QC enzyme-linked method,the inhibitory effect of 16 kinds of traditional Chinese medicine methanol extracts such as Eucommia ulmoides on QC was studied.The results showed that extracts of Chinese herbal medicines such as Eucommia,Cinnamon,Eclipta prostrata,Epimedium,and Paeonia can be used.Significant inhibition of QC activity.(2)Using double-transgenic AD mice(APP/PS1)as a model,the anti-AD effects of cinnamon and paeonol extracts were studied preliminarily.The behavioral experiments and techniques such as open field experiment and T-type water maze were used to study.The differences in activity,cognitive ability and memory ability of AD mice in each group showed that the mice in each group had improved abilities;(3)GD-QC enzymelinked assay and ELISA methods were used.The inhibitory effect of the two extracts on QC in AD mice showed that the cinnamon extract had a good inhibitory effect on QC,and could significantly inhibit the formation of p E-Aβ and the formation of total Aβ plaques in the brain;The effect of QC inhibition on mouse brain was not obvious,but it could still inhibit the formation of p E-Aβ and the formation of total Aβ plaque.(4)The cerebral hemisphere,cortex,hippocampus,kidney,The spleen tissue homogenate supernatant,serum IL-6,TNF-α,IL-1β,IFN-γ content,the results showed that the immune factor content of the two groups of mice were lower than the control group,indicating two traditional Chinese medicines The extract has a certain alleviating effect on inflammation in the body.The above studies indicate that the antiAD effect of cinnamon and paeonol extract is related to inhibition of QC activity,reduction of p E-Aβ production,and relief of inflammation in vivo.In summary,various studies have shown that targeting QC active substances can reduce the production of p E-Aβ in vivo by inhibiting QC activity,and then reduce the inflammatory response of brain neurons and exert anti-AD effects.This study will help to better understand the anti-AD mechanism of QC inhibitors,and actively promote the discovery of targeted QC anti-AD drugs.