Dataset Information

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 ?-protein (A?) 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 A? 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.

SUBMITTER: Ou Z

PROVIDER: S-EPMC7176648 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Ou Zihao Z Deng Lulu L Lu Zhi Z Wu Feifan F Liu Wanting W Huang Dongquan D Peng Yongzheng Y

Nutrition & diabetes 20200422 1

<h4>Objective</h4>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 intest ...[more]

PMID: 32321934

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Project description:Gamma oscillations (20-50Hz) are a common local field potential signature in many brain regions that are generated by a resonant circuit between fast-spiking parvalbumin (PV)-positive interneurons and pyramidal cells. Changes in the magnitude and frequency of gamma have been observed in several neuropsychiatric disorders. However, it is unclear how disruptions in gamma oscillations affect cellular pathologies seen in these disorders. Here, we investigate this using the 5XFAD mouse model of Alzheimer’s disease (AD) and find reduced power and magnitude of behaviorally driven gamma oscillatory activity — even before the onset of plaque formation or measurable cognitive decline. Because of the early onset, we aimed to determine if exogenous manipulations of gamma could influence the progression of disease pathology. We find that driving PV-positive neurons at gamma frequency (40Hz) using channelrhodopsin-2 reduced total levels of amyloid-β (Aβ) 40 and 42 isoforms in the hippocampus of 5XFAD mouse. Driving PV-positive neurons at other frequencies, or driving excitatory neurons, did not reduce Aβ levels. Furthermore, driving PV-positive neurons reduced enlarged endosomes in hippocampal neurons and cleavage intermediates of APP in 5XFAD mouse. Gene expression profiling revealed a neuroprotective response with morphological transformation of microglia and markedly increased phagocytosis of Aβ by microglia. Inspired by these observations, we designed a non-invasive light-flickering paradigm that drives 40Hz gamma activity in mouse visual cortex. The light-flickering paradigm profoundly reduced Aβ40 and Aβ42 levels in the visual cortex of pre-symptomatic mice and greatly mitigated plaque load in the visual cortex of aged, symptomatic mice. This reduction was completely blocked by a GABA-A antagonist, providing further support for an essential role of GABAergic signaling in mediating neuroprotective gamma activity. Overall, our findings uncover a dramatic and previously unappreciated function of the brain’s endogenous gamma rhythms in reducing the production and increasing the clearance of Aβ peptides, whose accumulation is believed to drive the pathogenesis of AD.

Dataset Information

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

Objective

Methods

Results

Conclusion

Publications

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

Similar Datasets

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