A novel transgenic mouse line with hippocampus-dominant and inducible expression of truncated human tau  

作　　者：Yang Gao Yuying Wang Huiyang Lei Zhendong Xu Shihong Li Haitao Yu Jiazhao Xie Zhentao Zhang Gongping Liu Yao Zhang Jie Zheng Jian-Zhi Wang 

机构地区：[1]Department of Pathophysiology,Key Laboratory of Ministry of Education for Neurological Disorders,School of Basic Medicine,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [2]Department of Neurology,Renmin Hospital of Wuhan University,Wuhan 430030,China [3]Key Laboratory of Ministry of Education for Neurological Disorders,Department of Endocrine,Liyuan Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430077,China [4]Neuroscience Research Institute and Department of Neurobiology,School of Basic Medical Sciences,Peking University,Beijing,China [5]Key Laboratory for Neuroscience,Ministry of Education/National Health Commission,Peking University,Beijing 100083,China [6]Co-Innovation Center of Neuroregeneration,Nantong University,Nantong 226000,China

出　　处：《Translational Neurodegeneration》2023年第1期154-169,共16页转化神经变性病（英文）

基　　金：This study was supported in part by the Natural Science Foundation of China(82230041,91949205,31730035 and 81721005),the Fundamental Research Funds for the Central Universities(YCJJ202203019);National Key R&D Program of China(2016YFC1305800);Guangdong Provincial Key S&T Program(018B030336001).

摘　　要：Background Intraneuronal accumulation of hyperphosphorylated tau is a defining hallmark of Alzheimer’s disease(AD).However,mouse models imitating AD-exclusive neuronal tau pathologies are lacking.Methods We generated a new tet-on transgenic mouse model expressing truncated human tau N1-368(termed hTau368),a tau fragment increased in the brains of AD patients and aged mouse brains.Doxycycline(dox)was administered in drinking water to induce hTau368 expression.Immunostaining and Western blotting were performed to measure the tau level.RNA sequencing was performed to evaluate gene expression,and several behavioral tests were conducted to evaluate mouse cognitive functions,emotion and locomotion.Results Dox treatment for 1-2 months at a young age induced overt and reversible human tau accumulation in the brains of hTau368 transgenic mice,predominantly in the hippocampus.Meanwhile,the transgenic mice exhibited AD-like high level of tau phosphorylation,glial activation,loss of mature neurons,impaired hippocampal neurogenesis,synaptic degeneration and cognitive deficits.Conclusions This study developed a well-characterized and easy-to-use tool for the investigations and drug development for AD and other tauopathies.

关 键 词：Alzheimer’s disease Animal model Tau hyperphosphorylation Truncated tau Tet-on system 

分 类 号：R741[医药卫生—神经病学与精神病学]