Sorl1 knockout inhibits expression of brain-derived neurotrophic factor:involvement in the development of late-onset Alzheimer's disease  

作　　者：Mingri Zhao Xun Chen Jiangfeng Liu Yanjin Feng Chen Wang Ting Xu Wanxi Liu Xionghao Liu Mujun Liu Deren Hou 

机构地区：[1]Department of Neurology,The Third Xiangya Hospital of Central South University,Changsha,Hunan Province,China [2]Center for Medical Genetics&Hunan Key Laboratory of Medical Genetics,School of Life Sciences,Central South University,Changsha,Hunan Province,China [3]Department of Cell Biology,School of Life Sciences,Central South University,Changsha,Hunan Province,China

出　　处：《Neural Regeneration Research》2024年第7期1602-1607,共6页中国神经再生研究（英文版）

基　　金：supported by the Community Development Office of Hunan Provincial Science and Technology Department;China,Nos.2020SK53613(to DH),21JJ31006(to DH);the Fundamental Research Funds of Central South University,Nos.CX20220375(to TX),2023zzts215(to MZ)。

摘　　要：Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.

关 键 词：brain-derived neurotrophic factor late-onset Alzheimer’s disease N-methyl-D-aspartate receptor sortilin-related receptor 1 SYNAPSE 

分 类 号：R749.16[医药卫生—神经病学与精神病学]