Protective Effects Of Akkermansia Muciniphila In Mice Models With Alzheimer's Disease

Alzheimer's Disease(AD)is a disease behaved with dementia such as memory impairment,loss of visual skills,impairment of performance,and behavioral changes,which characterized by serious cognitive impairment and significant pathological changes in the brain.In recent years,a large number of reports indicated that metabolic syndrome,included obesity and insulin resistance,was a key high risk factor for cognitive impairment and dementia.Many studies had shown that the development of insulin resistance in the brain appeared in AD patients,which was associated with multiple pathological features.Therefore,many scholars believed that cerebral insulin pathway was part of the causes of AD,and to alleviate the impaired insulin pathway was a new strategy for prevention and treatment of AD.Akkermansia muciniphila is the only representative gut microbes in the genus Verrugatus which can be cultivated and is one of gut microbes in the human that can be easily detected by metagenomic analysis.To detect the content of Akk bacteria in different populations,it could be found that the abundance of the bacteria in the intestine of patients with type 2 diabetes was significantly reduced.Moreover,animal experiments also showed that Akk could prevent the weight gain with high-fat diet,repaired the damaged integrity of the epithelium barrier,reduced endotoxin levels in blood and thereby improved insulin resistance in animals.The abundance of Akk in the gut of AD animal models also decreased significantly.Therefore,we hypothesized that Akk could alleviate the host endotoxemia,chronic inflammatory response and insulin resistance,thereby improving development of AD,which might open up a new approach for the treatment of AD.1.Objectives:1.1 To explore whether Akk can improve glucose and lipid disorders,repair intestinal barrier in AD model mice and the mechanisms of action.1.2 To explore the protective effects of Akk on cognitive impairment,amyloid deposition in AD model animal and the mechanisms of action.2.Methods2.1 animals and grouping40 three-month-old APP/PS1 positive male mice were randomly divided into 4 groups(high fat diet + Akk group,high fat diet + PBS group,normal diet + Akk group,normal diet + PBS group);12 three-month-old APP/PS1 negative male mice were divided into 2 groups(normal diet + Akk group,normal diet + PBS group).Experimental groups were given 2 × 109CFU/0.2ml/day dose of Akk gavage,the control groups were given the same volume of PBS.The entire experiment period lasted for 6 months.2.2 Fasting blood glucose and oral glucose tolerance test were measured in mice2.3 DAO levels in mouse serum and colonic mucus cells were measured in mice2.4 The serum ALT,AST,total cholesterol and triglyceride levels in mice were measured,and liver and scapular adipocytes in mice were examined.2.5 MRI examination2.6 amyloid ?-protein(A?)expression in mice brain were measured.2.7 Spatial learning and memory ability and cognitive ability in mice were measured.2.8 Statistical analysis3.Results:3.1 Akk could effectively reduce the fasting blood glucose and serum diamine oxidase levels,and alleviate the reduction of colonic mucous cells in AD model mice.3.2 Akk did not improve weight gain of AD model mice,but could effectively reduce blood lipid levels,improve hepatic steatosis and spacular brown fat whitening.3.3 Akk could reduce hippocampal A? protein deposition and cerebral cortex A?40-42 levels.3.4 Akk could reduce the study time and improve the correct rate of Y maze tests in AD model mice,and effectively alleviated the damage of cognitive ability.4.Conclusion:4.1 Akk could effectively improve impaired glucose tolerance and intestinal barrier injury in AD model mice.4.2 Akk could alleviate dyslipidemia in AD model mice.4.3 Akk could slow down the pathological changes of brain in AD model mice.4.4 Akk could alleviate the impairment of spatial learning ability and memory ability in AD model mice.