p85S6K sustains synaptic GluA1 to ameliorate cognitive deficits in Alzheimer’s disease  

作　　者：Jia-Bing Li Xiao-Yu Hu Mu-Wen Chen Cai-Hong Xiong Na Zhao Yan-Hui Ge Hao Wang Xiao-Ling Gao Nan-Jie Xu Lan-Xue Zhao Zhi-Hua Yu Hong-Zhuan Chen Yu Qiu 

机构地区：[1]Department of Pharmacology and Chemical Biology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [2]Institute of Interdisciplinary Integrative Biomedical Research,Shuguang Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 201210,China [3]Collaborative Innovation Center for Brain Science,Department of Anatomy and Physiology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

出　　处：《Translational Neurodegeneration》2023年第1期890-907,共18页转化神经变性病（英文）

基　　金：supported by the National Natural Science Foundation of China(81802840,81473217);Shanghai Natural Science Foundation(20ZR1430100);Shanghai High Level Local University Construction Project(PT21002).

摘　　要：Background Ribosomal protein S6 kinase 1(S6K1)is a serine-threonine kinase that has two main isoforms:p70S6K(70-kDa isoform)and p85S6K(85-kDa isoform).p70S6K,with its upstream mammalian target of rapamycin(mTOR),has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer’s dis-ease(AD).However,the function of p85S6K has long been neglected due to its high similarity to p70S6k.The role of p85S6K in learning and memory is still largely unknown.Methods We fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K.Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor.The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence,Western blot,in situ proximity ligation assay,morphological staining and behavioral examination.Further,the expression level of p85S6K was measured in brains from AD patients and AD model mice.Results p85S6K,but not p70S6K,was enriched in the postsynaptic densities.Moreover,knockdown of p85S6K resulted in defective spatial and recognition memory.In addition,p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150.Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in syn-apses,thus sustaining synaptic function and spine densities.Moreover,p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice.Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice.Conclusions These results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1.The findings provide an insight into the r

关 键 词：Alzheimer’s disease COGNITION GluA1 subunit of AMPA receptors Ribosomal S6 protein kinase 1 85 kDa isoform 

分 类 号：R749.16[医药卫生—神经病学与精神病学]