The Effects Of Gastric Bypass Surgery On Cognitive Function Of Alzheimer’s Disease Model Mice And Study Of Its Mechanism Of Action

Objective: Studies have shown that there is a relationship between the intestine and the brain that interacts and communicates,and the " Gut microbes-gut-brain axis" theory has been proposed.Based on this theory,this experiment is the first study to investigate the effect of gastric bypass surgery on cognitive function in Alzheimer’s disease model mice,and to initially investigate the gut microbes and T1R2 /T1R3-SGLT-1-GLP-1 / GLP-2 endocrine signaling pathway plays a role in it.Finally,we also studied the relationship between Alzheimer’s disease and brain SGLT-1expression,hoping to find an effective target for the treatment of Alzheimer’s disease.Methods: Two males and two females of APP / PS1 / Tau three transgenic(AD)mice were bred and breeded in an SPF-grade animal laboratory at the Animal Experiment Center of Renmin Hospital of Wuhan University,then,take offspring male mice for animal grouping: use random number table method to divide AD model group(AD)and AD gastric bypass surgery group(ADSS),in addition,take C57 normal male mice,randomly divide WT normal control Group(WT)and WT gastric bypass surgery group(WTSS),a total of 4 groups,6 in each group,each 6 months old,male and female,weighing 22-25 g.In the ADSS group and the WTSS group,gastric bypass surgery was performed under the same conditions,and the other two groups did not have any intervention and had a normal diet.Two months after gastric bypass surgery,a water maze experiment was used to evaluate the cognitive behavior of the four groups of mice.After the completion of the water maze experiment,the mice were killed,and the blood samples of each group of mice were collected by using the eyeball blood collection method.The serum was separated using a centrifuge,while the hippocampus and proximal small intestine(duodenum and jejunum)tissue,stored in-80 ° C refrigerator for subsequent experiments.In addition,a part of hippocampal tissue in each group was stored in 4% paraformaldehyde for experiments.Finally,Western blot was applied to detect the expression levels of T1R2,T1R3 and SGLT-1in the proximal small intestine of each group of mice,as well as the expression levels of GLP-1R,SGLT-1 and Tau protein phosphorylation in hippocampus.Immunofluorescence was used to detect the expression of GLP-2R in hippocampal tissues of each group.ELISA test was used to detect the expression of GLP-1 and GLP-2 in serum of mice in each group.HE staining was used to observe the neuronal cell morphology of the hippocampus in each group of mice.Results: 1.Compared with the AD group,the escape latency of the ADSS group was significantly shortened and the number of crossing platforms was significantly increased,and the difference was statistically significant.2.Compared with AD group,Tau protein phosphorylation level in ADSS group was significantly reduced,and the difference was statistically significant.3.Compared with the AD group,the neuronal cells in the CA1 area of the hippocampus in the ADSS group were basically normal in shape,with neatly arranged cells and tight structure.Only a small number of nuclei contracted and the number of necrotic cells was significantly reduced.4.Compared with the AD group,the small intestine T1R2,SGLT-1 protein expression,serum GLP-1,GLP-2 levels,hippocampal GLP-1R,GLP-2R protein levels in the ADSS group were significantly increased,and the differences were all statistically significant.However,there was no statistically significant difference in the expression of T1R3 in the small intestine.5.Compared with the AD group,the protein expression of SGLT-1 in the hippocampus of ADSS group was significantly increased,and the difference was statistically significant.Conclusions: 1.Roux-en-Y gastric bypass surgery can improve the cognitive function of Alzheimer’s disease model mice.2.Roux-en-Y gastric bypass surgery can improve the cognitive function of AD mice by regulating the T1R2 / T1R3-SGLT-1-GLP-1 / GLP-2 endocrine signaling pathway,and gut microbes may play a mediating role in it.3.Alzheimer’s disease is related to the expression of SGLT-1 in the brain.Brain SGLT-1 may become a new target for the treatment of Alzheimer’s disease.