| In recent years,the global aging problem continues to aggravate,which was accompanied by various diseases of the old.Improving elderly health is the core strategy to deal with aging.Among them,Alzheimer’s disease(AD)is one of the major diseases seriously endangering the health and life quality of the elderly worldwide.AD is a neurodegenerative disease caused mainly by neurofibrillary tangles formed by the hyperphosphorylation of Tau protein in nerve cells and abnormal accumulation of extracellular amyloid-β(Aβ).It is characterized by cognitive impairment and mood abnormalities.Studies have demonstrated that gut microbes exert a significant influence on the function of the central nervous system through the "gut-brain axis".Alterations in the gut microbiota have been linked to neurological disorders,including autism spectrum disorders,AD,and Parkinson’s disease.Konjac mannose oligosaccharide(MOS)is a kind of high-efficiency prebiotics,which is mainly obtained by enzymatic hydrolysis in konjac,a natural green plant.Previous studies have shown that MOS have biological activities such as antioxidant,anti-inflammatory,immune enhancement,and gut microbiota regulation.However,there are few reports on the neuroprotective function and potential mechanisms of MOS.Given that,the classic 5xFAD mouse model of AD was selected in this study.This study aimed to explore the effect of MOS on cognitive dysfunction in mice with AD.We hope to provide a theoretical basis for the study of MOS as a nutritional supplement in the improvement of neurodegenerative diseases.The main research and results are as follows:(1)In this study,6-month-old male 5xFAD mice were treated with MOS(0.12%,w/v)in drinking water for 8 weeks to investigate the effects of MOS on cognitive impairment and brain function.The results showed that MOS significantly reduced the loss of spatial memory,and improved anxiety-like and obsessive-compulsive behavior in 5xFAD mice.Immunofluorescence staining and q RT-PCR showed that MOS inhibited the expression of amyloid precursor protein and β-secretase,thus inhibiting the production of amyloid protein.Besides,MOS significantly inhibited the activation of microglia,decreased the expression of inflammatory cytokines,and inhibited oxidative injury in the brain of 5xFAD mice.We also found that MOS significantly reduced the levels of corticosterone and corticotropin-releasing hormone in 5xFAD mice,and upregulated norepinephrine expression,thereby improving hypothalamic-pituitary-adrenal(HPA)axis dysfunction.(2)16S r RNA sequencing analysis was conducted to investigate the effects of MOS on gut microbiota and its metabolites in 5xFAD mice.It was found that MOS supplementation significantly increased the relative abundance of Lactobacillus,and butyrate-producing bacteria Clostridium pasteurianum and Lachnospira,while significantly reduced the relative abundance of harmful bacteria Helicobacter.Histopathological studies also showed that MOS treatment significantly improved the gut barrier damage in 5xFAD mice and increased the m RNA expression of intestinal tight junction proteins Claudin-1 and ZO-1.Besides,the results showed that MOS treatment significantly increased the expression of short-chain fatty acid receptors FFAR2/3 in colon tissues.The content of short-chain fatty acids(SCFAs)in feces and serum of 5xFAD mice was determined by gas chromatography.The results showed that the supplementation of MOS significantly increased both of them,especially the level of butyrate.Most importantly,correlation analysis showed that the remodeled microbiota and butyrate levels were significantly associated with behavioral changes and brain redox levels in mice.(3)To further explore the mechanism of SCFAs in improving brain function,6-month-old male 5xFAD mice were also selected to treat with SCFAs in drinking water for8 weeks.As expected,SCFAs treatment had the same effect on 5xFAD mice as the supplementation of MOS.SCFAs treatment significantly improved the behavior disorders of5 x FAD mice,inhibited the accumulation of amyloid protein in the brain,suppressed neuroinflammation and oxidative damage,and accompanied with balanced the expression of HPA axis-related hormones.These results suggested that the "microbiota-SCFAS-brain" axis plays an important role in improving neuroinflammation,oxidative stress,and HPA axis function in the central nervous system,which may be the potential mechanism of the neuroprotective function of MOS.The study demonstrated that supplementation with MOS improved cognitive deficits and other behavioral disorders in 5xFAD mice by reshaping gut microbial composition and increasing SCFAs content,which also provides a theoretical basis for developing a new prebiotics targeting therapy for metabolic and neurodegenerative diseases. |
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