Zinc On Endoplasmic Reticulum Stress-mediated Chronic Stress-induced Aβ Deposition In The Hippocampus Of APP/PS1 Mice And Its Mechanism

Objective: To investigate the effect of different doses of zinc intake on the learning and memory ability of APP/PS1 mice induced by prenatal chronic stress combined with offspring chronic stress and its possible mechanism.Methods: 1)Pregnant mice were divided into prenatal chronic stress group and prenatal normal group,and 56 offspring male mice carrying the APP/PS1 double transgenic model were selected.group,namely prenatal normal-offspring normal group(normal control group,n=8),prenatal chronic stress-offspring normal group(CPS group,n=8),prenatal normal-offspring chronic stress group(COS group,n=8),prenatal chronic stress-offspring chronic stress control group(CPS+COS control group,n=8),prenatal chronic stress-offspring chronic stress-low zinc dose group(CPS+COS+Zn-L group,n=8),prenatal chronic stress-offspring chronic stress-medium zinc dose group(CPS+COS+Zn-M group,n=8),prenatal chronic stress-Offspring chronic stress-high zinc dose group(CPS+COS+Zn-H group,n=8).The APP/PS1 mice in the 6-month-old zinc intervention group and the COS+CPS control group were subjected to chronic stress for 3 months,and different doses of zinc were added to the intervention group through drinking water during the stress;2)Morris water maze test and Y maze test were used to detect the learning and memory ability of mice;3)HE staining was used to observe the pathological changes of neurons in hippocampal CA3area;4)The expression levels of Aβ1-40 and Aβ1-42 were detected by ELISA;5)Western blot was used to detect the expression levels of p-PERK,GRP78,BACE1 and p-e IF2α in the hippocampus of APP/PS1 mice in each group.Results: 1)The results of the Morris water maze test indicated that,compared with the control group,the escape latency of the COS group,the CPS group and the COS+CPS control group was significantly longer,and the number of cross-platforms was less(P <0.01).Compared with the control group,the escape latency of CPS+COS+Zn-H group,CPS+COS+Zn-M group and CPS+COS+Zn-L group gradually decreased,and the number of cross-platform was more(P<0.01);2)The Y-maze results showed that compared with the control group,the COS group,CPS group and the COS+CPS control group required longer training latency and fewer correct times(P<0.01),compared with the COS+CPS control group,CPS+COS+Zn-H group,CPS+COS+Zn-M group,CPS+COS+Zn-L group decreased the latency time required for training and increased the correct number of times(all P<0.01);3)HE staining results showed that compared with the control group,the nerve cells in the COS group,CPS group and COS+CPS control group were deformed,necrotic and structurally disordered;CPS+COS+Zn-H group,CPS+COS+Zn-H group,CPS+COS+ZnWith the increase of zinc dose in M group and CPS+COS+Zn-L group,the damage of nerve cells in hippocampus was alleviated;4)ELISA results showed that compared with the control group,the expression levels of Aβ1-40 and Aβ1-42 in the hippocampus of the COS group,CPS group and COS+CPS control group were significantly increased(P<0.01),and the COS+CPS control Compared with the control group,the expressions of Aβ1-40 and Aβ1-42 in each dose group were gradually decreased(P<0.01);5)Western Blot results showed that,compared with the control group,the COS group,CPS group,CPS+COS The expressions of BACE1,GRP78,p-e IF2α and p-PERK in the hippocampus of the mice in the group were significantly increased.Compared with the COS+CPS control group,the expressions of BACE1,GRP78,p-e IF2α,p-The expression level of PERK decreased gradually(P<0.05),and there was no significant difference between the different dose groups(P>0.05).Conclusions: 1)Prenatal chronic stress combined with offspring chronic stress aggravates the impairment of learning and memory in APP/PS1mice;2)Zinc supplementation within a certain dose range can alleviate the impairment of learning and memory ability of APP/PS1 mice caused by prenatal chronic stress combined with offspring chronic stress;3)Zinc alleviates Aβ deposition by interfering with PERK signaling pathway in endoplasmic reticulum stress.