Distinct Rab7-related Endosomal-Autophagic-Lysosomal Dysregulation Observed in Cortex and Hippocampus in APPswe/PSEN1dE9 Mouse Model of Alzheimer＇s Disease  

作　　者：Li Ba Xiao-Hua Chen Yan-Lin Chen Qing Nie Zhi-Jun Li Feng-Fei Ding Min Zhang 

机构地区：[1]Department of Neurology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China [2]Department of Neurology, Huangshi Central Hospital, Huangshi, Hubei 435000, China [3]Department of Neurology, Wuhan Central Hospital, Wuhan, Hubei 430014, China

出　　处：《Chinese Medical Journal》2017年第24期2941-2950,共10页中华医学杂志（英文版）

基　　金：This work was supported by a grant of National Natural Science Foundation of China （No. 81271406）.

摘　　要：Background：Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer＇s disease （AD）.Dysregulation of the endosomal-autophagic-lysosomal （EAL） pathway,which impairs amyloid precursor protein processing,is one of the earliest changes in AD.However,the precise role of EAL pathway in neurodegeneration remains unclear.This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction.Methods：We used 3-,7-,and 12-month-old APPswe/PSEN1dE9 （APP/PS1） mice to model different stages of AD with age-and gender-matched wild-type littermates as controls （4-7 mice per group） and detected the changes of EAL markers,endosomal organizers Rab5 and Rab7,autophagosome marker LC3B,and lysosomal proteins Lamp 1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis.To further explore the mechanism of EAL dysregulation in AD,components of the class Ⅲ phosphatidylinositol 3-kinase （PI3KC3） complex,activators ofRab7 （Beclin1 and UVRAG）,and the negative regulator of Rab7 （Rubicon） were also measured in this two brain regions.Results：In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly,EAL pathway,and related PI3KC3 members,UVRAG and Beclin1 were upregulated both in cortex and hippocampus （all P 〈 0.05）.By the age of 12 months old,when abundant amyloid plaques formed,EAL markers,UVRAG,and Beclin 1 were also upregulated in the cortex （all P 〈 0.05）.However,Rab7 was decreased significantly （P =0.0447）,accompanied by a reduction of its activating PI3KC complex component Beclin1 （P =0.0215） and enhancement of its inhibiting component Rubicon （P =0.0055） in the hippocampus.Conclusions：Our study implies that EAL pathway,represented as Rab7 and its PI3KC3 regulators＇ expressions,showed temporal and spatial variation in brains at different stages of AD.It provides new insights into the role of EAL pathway in pathogenesis and indicates potBackground：Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer＇s disease （AD）.Dysregulation of the endosomal-autophagic-lysosomal （EAL） pathway,which impairs amyloid precursor protein processing,is one of the earliest changes in AD.However,the precise role of EAL pathway in neurodegeneration remains unclear.This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction.Methods：We used 3-,7-,and 12-month-old APPswe/PSEN1dE9 （APP/PS1） mice to model different stages of AD with age-and gender-matched wild-type littermates as controls （4-7 mice per group） and detected the changes of EAL markers,endosomal organizers Rab5 and Rab7,autophagosome marker LC3B,and lysosomal proteins Lamp 1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis.To further explore the mechanism of EAL dysregulation in AD,components of the class Ⅲ phosphatidylinositol 3-kinase （PI3KC3） complex,activators ofRab7 （Beclin1 and UVRAG）,and the negative regulator of Rab7 （Rubicon） were also measured in this two brain regions.Results：In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly,EAL pathway,and related PI3KC3 members,UVRAG and Beclin1 were upregulated both in cortex and hippocampus （all P 〈 0.05）.By the age of 12 months old,when abundant amyloid plaques formed,EAL markers,UVRAG,and Beclin 1 were also upregulated in the cortex （all P 〈 0.05）.However,Rab7 was decreased significantly （P =0.0447）,accompanied by a reduction of its activating PI3KC complex component Beclin1 （P =0.0215） and enhancement of its inhibiting component Rubicon （P =0.0055） in the hippocampus.Conclusions：Our study implies that EAL pathway,represented as Rab7 and its PI3KC3 regulators＇ expressions,showed temporal and spatial variation in brains at different stages of AD.It provides new insights into the role of EAL pathway in pathogenesis and indicates pot

关 键 词：Autophagy Class III Phosphatidylinositol 3-Kinase Complex ENDOCYTOSIS NEURODEGENERATION Rab7 

分 类 号：R0[医药卫生]