| 1.Purpose of the study Alzheimer’s Disease AD（AD）is an important factor in the global aging population,and the incidence of AD is rapidly increasing in our country.It is a serious central neurodegenerative disease that is a tremendous stressor for the whole society and everyone’s family.However,there is no treatment available for AD,and its etiology is still unknown.the expression of IL-1β indicator（Interleukin-1β,IL-1β）in the brain and serum of AD patients is significantly increased,and its possible mechanism of inducing neurogenic neurological damage has consequently attracted the attention of researchers.The results of many experiments suggest that activation of the inflammatory factor IL-1β and the cell scorch-related proteins GSDMD and GSDMD-N in tissues is the main cause of AD pathogenesis.In this study,by observing the effects of HIIT on cognitive dysfunction in transgenic model mice,and by detecting the changes in serum levels of inflammation-related factor IL-1β as well as inflammation-related factor IL-1β and cell scorch death-related proteins GSDMD and GSDMD-N in hippocampal region,we aimed to investigate the effects of HIIT on cognitive dysfunction in Alzheimer’s disease and its possible therapeutic mechanisms,and to preliminarily To explore whether the positive effect of HIIT on AD is related to cellular scorch death,which lays the foundation for the clinical application in Alzheimer’s disease.2.Research methods Twelve 6-month-old adult C57 male mice,as wild control group（WC）,and 24 6-month-old male APP/PS1 transgenic model mice were randomly divided into 12 of them as transgenic model control group（NC）,and the other 12 as high-intensity interval training group（H）.3 d after adaptation feeding of group H,they started to follow the developed high-intensity interval training program on a treadmill The training consisted of a 5-min warm-up at the beginning,a formal training and a 5-min recovery at the end.The mice in the training group warmed up and recovered at 40% Smax,and the mice in the training group were formally trained at 85% Smax for 1.5 min of high-intensity running,followed by 45% Smax for 2 min of active recovery,for a total of 8 groups,with a total time of 41.5 min.Training was performed every other day for a total of 8 weeks of training intervention.After the 8-week intervention,the Morris water maze was used to detect changes in learning memory and spatial exploration ability in APP/PS1 transgenic mice;HE staining was used to detect morphological differences in hippocampal neurons in each group;enzyme-linked immunoassay kits were used to determine the content of IL-1β in mouse serum samples;immunoblotting was used to detect IL-1β,GSDMD,and GSDMD.1β,GSDMD,GSDMD-N protein content by immunoblotting.All data were statistically analyzed using SPSS25.0,and the results were expressed as mean±standard deviation（mean±SD）,and one-way analysis of variance（ANOVA）was used for comparison between multiple groups.The non-parametric test was chosen for data that were not normally distributed.P < 0.05 indicates that the difference is statistically significant,and P < 0.01 indicates that the difference is highly significant.3.Study results 3.1 Water maze detection results（1）Positioning voyage: 1)Mean escape latency: The mean escape latency tended to decrease over time in all groups,but it decreased more slowly in the transgenic model group,while the escape latency in the wild-type control and HIIT groups showed a significant decrease.Both wild-type control and HIIT groups had lower escape latencies than the transgenic model group for the same intervention cycle.There was no significant difference between all groups of mice on the first day compared with each other（P>0.05）;from the second day onwards the transgenic model group was significantly longer compared with the wild control group（P<0.01）,the HIIT group was not significantly different from the wild control group on the second day（P>0.05）,and the HIIT group was significantly shorter compared with the transgenic model group（P<0.05）;the wild control group and HIIT group both showed a significant decrease on the third day（P<0.05）;the wild control group showed a highly significant difference on the fourth day（P<0.01）;the HIIT group showed a highly significant difference on the fifth day（P<0.01）;there was no statistical difference between the NC group before and after comparison（P>0.05）.2)Target quadrant dwell time: the target quadrant dwell time of all groups of mice changed with time（2）Target quadrant dwell time: The target quadrant dwell time of all groups of mice showed a tendency of prolongation over time,but the mice in the transgenic model group showed a slow tendency of prolongation,while the target quadrant dwell time of the wild control and HIIT groups showed a significant tendency of prolongation.The target quadrant dwell time on the same day was higher in both wild control and HIIT groups than in the transgenic model group.There was no significant difference between mice in each group on days 1-5（P>0.05）,no significant change in the dwell time in the fourth quadrant in each group,and no statistical difference between the WC,NC and H groups before and after comparison（P>0.05）;（2）spatial exploration: the number of platform crossing was significantly lower in the transgenic model group than in the wild control group（P<0.01）,while significantly more in the HIIT group than in the transgenic model group（P<0.01）,although less than the wild control group,the difference between them was not significant（P>0.05）,but the target quadrant dwell time increased significantly and was not statistically significant（P>0.05）.8 weeks after the completion of the intervention,the HIIT group had a significantly shorter escape latency and a significantly higher number of original platform searches,and the difference was statistically significant compared with the transgenic model group（P<0.01）.3.2 Pathological staining results HE staining: wild control mice had many ordered neuronal cells with distinct nuclei and centered nuclei,without edema and inflammatory cell invasion.In the hippocampal C1 region,there were a small number of neuronal cells missing,the organization of the cells was unclear,and the nuclei were deeply stained and coagulated.This suggests brain tissue damage after experimental cerebral ischemiareperfusion.there was a small infiltration of nuclei within the experimental cells in the HIIT group.The results showed a significant correlation of apoptosis in the hippocampal region of pyramidal cells in different control groups.3.3 Results of enzyme-linked immunoassay The HIIT group was able to reduce the expression of IL-1β factor in APP/PS1 transgenic model mice,IL-1β: significant difference（P < 0.01）in the transgenic model group compared with the wild control group,and significantly lower（P < 0.05）in the HIIT group compared with the transgenic model group.3.4 Immunoblotting results The HIIT group was able to reduce the expression of inflammation-related factor IL-1β and cell scorch death-related proteins GSDMD and GSDMD-N terminus in the hippocampus of APP/PS1 transgenic model mice.IL-1β index: the content in the hippocampus of the transgenic model group was significantly higher compared with that of the wild control group（P < 0.05）,and the HIIT group had a tendency to significantly decrease compared with that of the transgenic model group.The differences were statistically significant（P < 0.05）;GSDMD index: the transgenic model group showed a significant increase compared with the wild control group（P < 0.05）,and the HIIT group showed a significant decrease compared with the transgenic model group,and the differences were significant（P < 0.05）;GSDMD-N index: the transgenic model group showed a significant increase compared with the wild control group,and the HIIT group showed a significant decrease compared with the transgenic model group,and the differences were statistically significant（P < 0.05）.The differences were statistically significant（P < 0.05）.4.Conclusion of the study 4.1 High-intensity interval training therapy can effectively improve the spatial learning and memory abilities of APP/PS1 transgenic model mice.4.2 High-intensity interval training therapy can effectively improve brain tissue damage in APP/PS1 transgenic model mice.4.3 high-intensity interval therapy reduces serum production of the inflammatory cytokine interleukin-1β（IL-1β）in APP/PS1 transgenic model mice.4.4 High-intensity intermittent therapy reduces the expression of cell scorch deathrelated proteins GSDMD and GSDMD-N as well as inflammation-related protein IL-1β in brain tissue of APP/PS1 transgenic model mice,which may be one of the mechanisms by which high-intensity intermittent therapy exerts neuronal protective effects. |
PDF Full Text Request