The Effects Of M-?-glucan On AlCl₃-induced Learning And Memory Impairment In Mice And The Molecular Mechanisms

Background:Alzheimer's disease(AD),also known as Alzheimer's disease,is the most common chronic neurodegenerative disease,but its pathogenesis is still unclear and there is no effective medicine so far.It is urgent to develop effective anti-AD drugs.A preliminary study conducted by the team found that the polysaccharide D component(M-?-glucan)from the grifola frondosa bound to the innate immune receptor Dectin-1 to effectively improve the learning and memory damage caused by AlCl3.It can also increase the expression of glutamate excitatory receptor AMPA receptor(a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor,AMPAR),a key molecule of learning and memory in mouse brain tissue,and the expression of brain-derived neurotrophic factor(BDNF).However,the mechanisms for exerting the above pharmacological effects and regulating related signal molecules still need to be studied in detail.Based on the previous research results,the current study further explored the dose-dependent relationship of M-?-glucan in learning and memory,and molecular mechanisms and the morphological changes of brain tissue.Methods:In the chapter one,the C57 BL/6J mice(6-8 weeks old)were used to establish an animal model of learning and memory impairment induced by AlCl3(60 mg/kg,42 days).Normal saline was used as the negative control and Donepezil(2 mg/kg)as the positive control.M-?-glucan at different doses of 5,10 and 20 mg/kg was given by intraperitoneal injection for 42 days.The water maze navigation and space exploration experiments were performed to evaluate animal behavior,and the Hematoxylin-eosin,Franna Nissl,and Immunofluorescent stainings of hippocampal tissues was used for histology evaluation.Next,Western blot was used to detect the expression of Dectin-1,AMPA receptor,BDNF and other protein molecules,to explore the effect of M-?-glucan on learning and memory.In the chapter two,6-month-old C57 BL/6J APP/PSI double transgenic mice and the corresponding 6-month-old wild-type C57 BL/6J mice were used as the experimental subjects to explore the effect of M-?-glucan on learning and memory in APP/PSI double transgenic mice.The behavioral,histological,and protein chemistry indicators mentioned were detected.Results:After M-?-glucan treatment,the results of the first chapter showed that when compared with the AICI3 model group,the latency and swimming rate of the M-?-glucan administration groups were significantly shorter(p<0.05),and the number of crossing platforms increased significantly(p<0.05).The hippocampal tissue stained by HE and NS showed that M-?-glucan could effectively alleviate the tissue damage of hippocampal DG in mice.And Immunofluorescence staining showed that M-?-glucan inhibited the excessive activation of microglia and promoted neurogenesis.M-?-glucan at the dosage of 10 mg/kg showed the best abundant efficacy.The protein expression of Dectin-1,p-Akt,p-GSK-3? Ser9,AMPAR subunit GluAl,p-GluA1 Ser845,and brain-derived neurotrophic factor BDNF in mouse hippocampus were significantly increased after M-?-glucan administration.At the same time,M-?-glucan(5 and 10 mg/kg)effectively reduced the expression of phosphorylated Tau protein(p-Tau Ser396 and p-Tau Ser404)and TLR4 in the hippocampus.In the second chapter,we found that M-?-glucan had a certain effect on the learning and memory ability of APP/PSI double transgenic mice,but the therapeutic effect was not significant,and further research is necessary.Conclusion:M-?-glucan demonstrates the therapeutic effect on the learning and memory impairment induced by AlCl3,and the underlying mechanism is associated with the Dectin-1/TLR4/GSK-3? pathway,regulation of AMPA receptor,and neuroprotective molecule BDNF.