Identification of a compound that promotes synaptic function and ameliorates cognition deficits in APP/PS1 transgenic mice
作者单位：JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research Jinan University
会议名称：《中国神经科学学会第十二届全国学术会议》
会议日期：2017年
学科分类：1002[医学-临床医学] 100203[医学-老年医学] 10[医学]
基 金：supported in part by the National Natural Science Foundation of China(Grant nos.81422012,31471046 and 8161101585) the Special Support(Te Zhi)Program of Guangdong Province,China
关 键 词：Alzheimer’s disease protein synthesis dendritic spines synapse novel object recognition
摘 要：Objective Alzheimer’s disease（AD） is a neurodegenerative disease characterized by progressive memory dysfunction and increasingly severe dementia. The most widely accepted hypothesis is that aggregation of β-amyloid（Aβ） leads to a series of devastating effects to the nervous system, such as synaptic failure and neuronal death. The current drug development for AD therapy is mainly designed to antagonize Aβ, but the effect on cognition would be limited if the synaptic function is not restored. It is recently found that protein synthesis（m RNA translation） is impaired in AD brain, which leads to insufficient synthesis of critical proteins for synaptic function and neuronal survival. Therefore, identification of compounds that has the ability to enhance protein synthesis in neurons will be beneficial for the restoration of synaptic function and memory in AD. We previously found a compound C6, which induces robust protein synthesis in neuronal cell lines. This study aims to test whether this compound promotes synaptic function in hippocampal neurons, and whether it restores the synaptic and memory defects in AD modeled mice. Methods A puromycin labeling method was performed to test protein synthesis;Immunofluorescence and western-blot were used to test the expression of synaptic proteins;APP/PS1 transgenic mice, a widely accepted mouse model of AD, was used to test the treatment effect of C6;novel object recognition test was used to test learning and memory of the mice. Results（1） C6 promoted de novo protein synthesis in hippocampal neurons;（2） C6 increased the expression of synapsin I and PSD95;（3） C6 promoted dendritic spine formation in hippocampal neurons which depended on translation;（4） C6 improved novel object recognition in APP/PS1 mice. Conclusion C6, through upregulating protein synthesis, promotes synaptic function in cultured neurons and restores cognition functions in APP/PS1 mice.