Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer's disease

Abstract

Objective: Alzheimer's disease (AD) is a global health problem without effective methods to alleviate the disease progression. Amyloid β-protein (Aβ) is widely accepted as a key biomarker for AD. Metabolic syndromes, including obesity and insulin resistance, are key high risk factors for AD. Akkermansia muciniphila (Akk), the only representative human gut microbe in the genus Verrucomicrobia, can prevent the weight gain caused by a high-fat diet, repair the damaged integrity of the intestinal epithelium barrier, reduce endotoxin levels in blood and improve insulin resistance. The aim of this study is to explore the impact of Akk administration in AD model mice in different diets.

Methods: APP/PS1 mice were fed either a normal chow diet or a high-fat diet and were treated with Akk by gavage each day for 6 months. The impacts of Akk on glucose metabolism, intestinal barrier and lipid metabolism in the mouse model of AD were determined. Changes in brain pathology and neuroethology were also analyzed.

Results: Akk effectively reduced the fasting blood glucose and serum diamine oxidase levels, and alleviated the reduction of colonic mucus cells in APP/PS1 mice. After treatment with Akk, the APP/PS1 mice showed obviously reduced blood lipid levels, improved hepatic steatosis and scapular brown fat whitening. Moreover, Akk promoted the reduction of Aβ 40-42 levels in the cerebral cortex of APP/PS1 mice, shortened the study time and improved the completion rate in Y-maze tests.

Conclusion: Akk effectively improved glucose tolerance, intestine barrier dysfunction and dyslipidemia in AD model mice. Our study results suggested that Akk could delay the pathological changes in the brain and relieve impairment of spatial learning and memory in AD model mice, which provides a new strategy for prevention and treatment of AD.

Fig. 1. Akkermansia muciniphila ameliorated glucose homeostasis and restored intestinal barrier function.

a, b Quantification of colonic mucus cells identified by periodic acid–Schiff reaction. c Serum DAO levels of the in vitro gut permeability assay. d Fasting serum glucose profile in the mice. e, f The mean area under the curve (AUC) was measured during an oral glucose tolerance test (OGTT). Data are presented as the mean ± SEM, N = 6–10 per group. *p < 0.05; **p < 0.01; ***p < 0.001.

Fig. 2. Akkermansia muciniphila ameliorated lipid metabolism disorders.

a Body weight gain and b daily food intake per mouse. c Serum TG and d Chol levels were measured in the mice. e, f Histological assessment of hepatic steatosis with representative pictures of H&E stained liver sections. g Representative H&E images of scapular adipose tissue deposits. h Representative western blot of scapular BAT lysates in the six groups. i UCP1 expression was quantified using Image-Pro Plus 6.0 software and UCP1 content of brown adipose tissue was analyzed by immunohistochemistry. Data are presented as the mean ± SEM, N = 6–10 per group. *p < 0.05; **p < 0.01; ***p < 0.001.

Fig. 3. Akkermansia muciniphila reduced Aβplaque deposits and Aβ levels in brains of APP/PS1 mice.

a Representative IHC images of the hippocampus from the mice. b Statistical analyses of the plaque burden. c Soluble Aβ40 and d Aβ42 were analyzed by ELISA in the cortex of APP/PS1 mice. Data are presented as the mean ± SEM, N = 6–10 per group. *p < 0.05; **p < 0.01; ***p < 0.001.

Fig. 4. Akkermansia muciniphila ameliorated cognitive impairment and anxiety-related behaviors in APP/PS1 model mice.

a, b The total time of learning and accuracy rate after 24 h of training in the Y-maze tests. c–e In the open-field tests, the time spent in the center and the total times of clearing and standing on the hind legs were monitored for each mouse. Data are presented as the mean ± SEM, N = 6–10 per group. *p < 0.05; **p < 0.01; ***p < 0.001.