| Aim:Many studies showed that synaptic damage induced by β-amyloid deposition and Tau protein hyperphosphorylation could result in brain neural network connection disorder and be closely related to the onset and the process of Alzheimer’s disease.Xanthoceraside is a kind of triterpenoid saponins monomers compound.Our previous results showed that xanthoceraside could significantly improve learning and memory impairment in intracerebroventricular injection of Aβ-42 mice,intracerebroventricular injection of streptozotocin rats and several other AD animal models,meanwhile,increase the hippocampal SYP and PSD95 protein expression,which indicated xanthoceraside may protect synapses and enhance the synaptic plasticity.However,the animal models mentioned above mostly are acute injury AD models,which have much difference with the slow onset clinical characteristics of Alzheimer disease(AD)and could only observe the short-term therapeutic effects of drugs.APP transgenic and APP/PS1 transgenic mice are currently accepted AD animal models exhibiting the representative pathogenesis,pathological changes and symptoms of AD patients and suitable to observe the long-term therapeutic effects of drugs.Therefore,on the basis of previous work,this paper adopted APP transgenic mice and APP/PS1 transgenic mice model to investigate the effects of xanthoceraside on learning and memory impairment and synaptic plasticity,meanwhile discuss the synaptic protection mechanism in terms of Aβ generation procession,Tau protein phosphorylation and dendritic spines regulatory proteins to further clarify the mechanism of xanthoceraside to improve learning and memory disorder and provide theoretical basis for anti dementia drug research and development.Methods7 months APP transgenic mice(same months C57BL/6 by contrast)were given xanthoceraside(0.02,0.08,0.32 mg/kg),denepozil(1.3 mg/kg)or distiled water as control for consecutive six months.We adopted Y maze,novel object recognition,Morris water maze,social interaction,elevated plus-maze test,forced swimming,step through test,etc to detect the learning and memory ability,social interaction ability and anxiety of mice.Transmission Electron microscopy(TEM)was used to observe the hippocampus neuron synaptic ultrastructure.Western blot was applied to assay the expression of synapse structure and regulation related proteins(SYP,PSD95,GAP-43,NogoA,BDNF,TrkB,ERK,PI3K,and AKT),Aβ generation related proteins(APP,ADAM 10,BACE,PS1),phosphorylated Tau proteins and GSK-3p.Aβ deposition was detected by immunohistochemical method.6 months APP/PS1 transgenic mice(same months C57BL/6 by contrast)were gived xanthoceraside(0.08,0.32 mg/kg)for three consecutive months.Novel object recognition and Morris water maze tests were used to confirm the effects of xanthoceraside to improve learning and memory impairment in model mice.Golgi-Cox method was applied to detect the hippocampus dendritic spines density and quantity;Western blot was used to assay the RAC1,RhoA,ROCK2,and Cofilin protein expression.Results13 months APP transgenic mice and 9 months APP/PS1 transgenic mice showed significant working memory,image identify memory and spatial learning and memory disorders in Y maze test,novel object recognition test,Morris water maze test and step through test.Model mice also showed notable decrease of active social interaction time in social interaction test,indicating the social interaction ability impairment.Compared with model group,xanthoceraside(0.08～0.32 mg/kg)significantly increased spontaneous alternation in Y maze test;improved preferential index and distinguish index to novel object in novel object recognition test;shorten escape latency and swimming distance in water maze test;increased social interaction time in social interaction test and increased escape latency in step through test.However,in forced swimming and elevated plus-maze test,the data in different groups showed no significant difference.All above suggest that xanthoceraside could significantly improve working memory disorder,image identify memory disorder,spatial learning and memory disorder,and social communication impairment in APP transgenic mice and APP/PS1 transgenic mice.After administration for six consecutive months,xanthoceraside significantly promoted synaptic related protein expression of SYP,PSD-95,GAP-43,but showed no impact on the expression of negative regulation protein NogoA compared with APP transgenic mice.Xanthoceraside dose dependently increased the expression of BDNF and phosphorylated TrkB and promoted the activation of downstream PI3K/Akt and ERK in hippocampus ofAPP transgenic mice.Therefore,xanthoceraside could improve synaptic plasticity with the associated mechanism to activate BDNF/PI3-K/Akt signaling pathway.Xanthoceraside significantly reduced Aβ plaque deposit in cerebral cortex and hippocampus,which may be related to lower hippocampal APP protein expression and increase ADAM10 expression.Xanthoceraside significantly inhibited GSK3β activation and reduced the hippocampus Tau protein Ser396,Ser404 and Thr204 phosphorylation level.Golgi-Cox staining results showed that density of dendritic spines significantly reduced,while xanthoceraside 0.08 mg/kg and 0.32 mg/kg treatment for 3 consecutive months significantly increased dendritic spines density in hippocampus of APP/PS]transgenic mice.Mechanism study found xanthoceraside significantly increased RAC1 protein expression;inhibited negative dendritic spines regulatory proteins RhoA,ROCK2 and Cofilin protein expression.ConclusionXanthoceraside significantly improved learning and memory disorder,meanwhile significantly increased the density of dendritic spines and elevated synaptic plasticity in hippocampus of APP transgenic mice and APP/PS1 transgenic mice.The mechanism may be related to promote the protein expression of BDNF/ERK/PI3K signaling pathways,meanwhile,reduce Aβ plaque deposition and phosphorylation of Tau protein which induce synaptic damage.The research results could offer scientific basis for the development of xanthoceraside as a new drug to prevent and treat AD. |
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