Eucommiae cortex polysaccharides ameliorates learning and memory deficits in Alzheimer's disease mice by modulating gut microbiota and glutamate metabolism

Abstract

Abstract Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is distinguished by impairments in learning and memory. The microbiota-gut-brain axis has emerged as a significant factor in the pathogenesis of Alzheimer's disease. Eucommiae cortex polysaccharides (EPs), one of the most abundant substances in the Eucommiae cortex, exhibit potential immunomodulatory and neuroprotective effects. In our study, we discovered that long-term intervention with EPs (0.25%, w/w in food) significantly improved learning and memory in 5×FAD mice, a well recognized mouse model for Alzheimer's disease. Additionally, EPs substantially reduce the generation and deposition of amyloid-beta (Aβ) plaques in AD Mice. EPs reshaped the composition of gut microbiota, increased the abundance of Erysipelotrichaceae, Allobaculum, Bacteroidota, and Muribaculaceae, which are related to gut immunity and short-chain fatty acids(SCFs) production that exert neuroprotective effects through the gut-brain axis. Furthermore, EPs administration was able to correct metabolic disorders in AD mice, particularly glutamate metabolism disturbances. Correlation analysis demonstrates a robust association between the restructuring of gut microbiota and alterations in glutamate metabolism. Importantly, EPs administration significantly inhibited neuroinflammation and restored the oxidative-antioxidative balance in the brains of AD mice, which are potential factors contributing to learning and memory impairments. Interestingly, EPs administration significantly activated autophagy. Our results demonstrate that EPs reshaped gut microbiota, corrected glutamate metabolism disturbances, and significantly alleviated learning and memory impairments in 5xFAD mice through the gut-brain axis. The natural extract EPs holds promising potential for the therapeutic management of neurodegenerative disorders.