RNA Interference Silencing of Glycogen Synthase Kinase 3β Inhibites Tau Phosphorylation in Mice with Alzheimer Disease

被引:22
作者
Bian, Hong [1 ]
Bian, Wei [2 ]
Lin, Xiaoying [1 ]
Ma, Zhaoyin [1 ]
Chen, Wen [1 ]
Pu, Ying [1 ]
机构
[1] Shandong Univ, Sch Med, Dept Neurol, Jinan Cent Hosp, 105 Jiefang Rd, Jinan, Shandong, Peoples R China
[2] Fourth Peoples Hosp Jinan, Dept Endocrinol, Jinan, Peoples R China
基金
中国国家自然科学基金;
关键词
Alzheimer disease; Glycogen synthase kinase 3 beta; Tau protein; Phosphorylation; AMYLOID-BETA-PEPTIDE; CEREBROSPINAL-FLUID; TRANSGENIC MICE; NEUROFIBRILLARY DEGENERATION; MOUSE MODEL; GSK-3-BETA; CATENIN; HYPERPHOSPHORYLATION; KINASE-3-BETA; EPIDEMIOLOGY;
D O I
10.1007/s11064-016-1960-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
To explore the effect of glycogen synthase kinase 3 beta (GSK-3 beta) silencing on Tau-5 phosphorylation in mice suffering Alzheimer disease (AD). GSK-3 beta was firstly silenced in human neuroblastoma SH-SY5Y cells using special lentivirus (LV) and the content of Tau (A-12), p-Tau (Ser396) and p-Tau (PHF-6) proteins. GSK-3 beta was also silenced in APP/PS1 mouse model of AD mice, which were divided into three groups (n = 10): AD, vehicle, and LV group. Ten C57 mice were used as control. The memory ability of mice was tested by square water maze, and the morphological changes of hippocampus and neuron death were analyzed by haematoxylin-eosin staining. Moreover, the levels of Tau and phosphorylated Tau (p-Tau) were detected by western blotting and immunohistochemistry, respectively. The lentivirus-mediated GSK-3 beta silencing system was successfully developed and silencing GSK-3 beta at the cellular level reduced Tau phosphorylation obviously. Moreover, GSK-3 beta silence significantly improved the memory ability of AD mice in LV group compared with AD group (P < 0.05) according to the latency periods and error numbers. As for the hippocampus morphology and neuron death, no significant change was observed between LV group and normal control. Immunohistochemical detection and western blotting revealed that the levels of Tau and p-Tau were significantly down-regulated after GSK-3 beta silence. Silencing GSK-3 beta may have a positive effect on inhibiting the pathologic progression of AD through down-regulating the level of p-Tau.
引用
收藏
页码:2470 / 2480
页数:11
相关论文
共 38 条
[1]   Alzheimer's Association Report 2011 Alzheimer's disease facts and figures [J].
Thies W. ;
Bleiler L. .
ALZHEIMERS & DEMENTIA, 2011, 7 (02) :208-244
[2]   Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease [J].
Augustinack, JC ;
Schneider, A ;
Mandelkow, EM ;
Hyman, BT .
ACTA NEUROPATHOLOGICA, 2002, 103 (01) :26-35
[3]   Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer's disease [J].
Barilar, J. Osmanovic ;
Knezovic, A. ;
Gruenblatt, E. ;
Riederer, P. ;
Salkovic-Petrisic, M. .
JOURNAL OF NEURAL TRANSMISSION, 2015, 122 (04) :565-576
[4]   The B cell antigen receptor regulates the transcriptional activator β-catenin via protein kinase C-mediated inhibition of glycogen synthase kinase-3 [J].
Christian, SL ;
Sims, PV ;
Gold, MR .
JOURNAL OF IMMUNOLOGY, 2002, 169 (02) :758-769
[5]   Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer's disease [J].
DaRocha-Souto, B. ;
Coma, M. ;
Perez-Nievas, B. G. ;
Scotton, T. C. ;
Siao, M. ;
Sanchez-Ferrer, P. ;
Hashimoto, T. ;
Fan, Z. ;
Hudry, E. ;
Barroeta, I. ;
Sereno, L. ;
Rodriguez, M. ;
Sanchez, M. B. ;
Hyman, B. T. ;
Gomez-Isla, T. .
NEUROBIOLOGY OF DISEASE, 2012, 45 (01) :425-437
[6]   ALZHEIMERS-DISEASE - TAU PROTEINS, THE PROMOTING FACTORS OF MICROTUBULE ASSEMBLY, ARE MAJOR COMPONENTS OF PAIRED HELICAL FILAMENTS [J].
DELACOURTE, A ;
DEFOSSEZ, A .
JOURNAL OF THE NEUROLOGICAL SCIENCES, 1986, 76 (2-3) :173-186
[7]   β-Amyloid impairs the regulation of N-methyl-D-aspartate receptors by glycogen synthase kinase 3 [J].
Deng, Yulei ;
Xiong, Zhe ;
Chen, Paul ;
Wei, Jing ;
Chen, Shengdi ;
Yan, Zhen .
NEUROBIOLOGY OF AGING, 2014, 35 (03) :449-459
[8]   Role of glycogen synthase kinase-3 in cell fate and epithelial-mesenchymal transitions [J].
Doble, Bradley W. ;
Woodgett, James R. .
CELLS TISSUES ORGANS, 2007, 185 (1-3) :73-84
[9]   Full reversal of Alzheimer's disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3 [J].
Engel, Tobias ;
Hernandez, Felix ;
Avila, Jesus ;
Lucas, Jose J. .
JOURNAL OF NEUROSCIENCE, 2006, 26 (19) :5083-5090
[10]   Tau-knockout mice show reduced GSK3-induced hippocampal degeneration and learning deficits [J].
Gomez de Barreda, Elena ;
Perez, Mar ;
Gomez Ramos, Pilar ;
de Cristobal, Javier ;
Martin-Maestro, Patricia ;
Moran, Asuncion ;
Dawson, Hana N. ;
Vitek, Michael P. ;
Lucas, Jose J. ;
Hernandez, Felix ;
Avila, Jesus .
NEUROBIOLOGY OF DISEASE, 2010, 37 (03) :622-629