| Objective:According to the beta-amyloid cascade hypothesis of Alzheimer's disease (AD),Aβis the main etiological factor of AD.Specially targeting Aβ,we have developed H102,a new medicine for AD.The purpose of this study was to observe the effect of H102 on AD and potential mechanisms through Aβ-(42)damaged cellular model and APP transgenic mouse model.Methods:1.To study the effect of H102 on nerve cell:(1)SY5Y cell was treated by H102 with different concentration.The cell survival rate was measured by MTT,and the dose-effect curve was made.(2)SY5Y cell were segregated into 3 groups:control group,Aβ42damaged group and Aβ42+H102 group,and MTT metabolic rate,LDH leakage rate and cell morphology were investigated respectively,2.To study the effect of H102 on APP transgenic mice: (1)The APP transgenic mice was randomly divided into model group,the low-dose(60μmol/L)H102 group and the high-dose(120μmol/L)group,and a group of C57BL/6J mice with the same age and background was set as normal control.The model group and the normal control group were treated with normal saline solution, while the H102 groups were treated with compounds(H102 in normal saline solution) of corresponding concentration.3μl medicine or saline was infused in lateral cerebral ventricle every day.20 days later,animal were killed and the brains were fixed. paraffin section of brains were used for senile plaques Congo red staining,and Aβ, synaptophysin,PSD-95,Shankl immunohistochemistry staining.A part of brain tissues were used to observe ultrastructure of neurons and synapsis on hippocampus CA1 domain.(2)In another experiment,a group of APP transgenic mice was conducted water maze testing,then 3βl H102(80μmol/L)was infused in lateral cerebral ventricle every day,20 days later,water maze testing was conducted again to investigate the behavior difference between before and after H102 treatment.Results:1.10～160umol/L H102 can increase the cell survival rate(P＜0.01),and in 20μmol/L H102 has optimal effection.Compared to control group,Aβ42damaged group showed reduced the cell survival rate(P＜0.05),increased LDH leakage rate(P＜0.01),diminished cell axon and amount of live cells.But H102 normalized the foregoing changes.2.(1)In model group,senile plaques can be observed in Cortex and hippocampus,and the expression of Aβincreasd,while the expression of synaptophysin,PSD-95 and Shank1 decreased.H102 treatment groups reduced senile plaques and normalize the expression of the targeted proteins.The effection of the high-dose group was more significant than that of the low-dose group and these labels in the high-dose group were similar to normal control.In model group neurons in hippocampal CA1 were dropsy,in which cell organs decreased,and spines and membrane in most of the chondriosome were fused and cloudy,a part of chondriosome were cavitating,Rough endoplasmic reticulum were degranulated,free ribosomes decreased,synaptic cleft were fused and cloudy,synaptic vesicle decreased under electron microscope.H102 treatment groups decreased pathological changes above.(2)Morris water maze test showed that the mean escape latent period(MELP) was obviously shorten after H102 treatment(p＜0.01).In space pilot test incipient angle,the times of traversing through flat roof,the times of traversing through coverage,the rate of the times and distances spanning target quadrant and the whole swimming times and distances had no significant difference between before and after H102 treatment.Conclusion:1.H102 can improve the survival rate of nerve cell, diminish neurotoxicity of Aβ,which indicate H102 has the neurotrophic and protectant function.2.H102 injected in lateral cerebral ventricle can prevent even reverse the production and aggregation of SP,decrease the expression of Aβ, increase the expression of synaptophysin,PSD-95 and Shankl in hippocampus and cortex,partly recover the structure of the neurons and synapsis,enhance synapse's plasticity,and improve space cognitive ability of APP transgenic mice.H102 is a potential drug for AD.
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