An App knock-in rat model for Alzheimer's disease exhibiting Aβ and tau pathologies, neuronal death and cognitive impairments

被引：83

作者：

Pang, Keliang ^{[1
,2
,3
]}

Jiang, Richeng ^{[4
,5
]}

Zhang, Wei ^{[6
,7
]}

Yang, Zhengyi ^{[8
]}

Li, Lin-Lin ^{[9
,10
]}

Shimozawa, Makoto ^{[4
]}

Tambaro, Simone ^{[4
]}

Mayer, Johanna ^{[4
]}

Zhang, Baogui ^{[8
]}

Li, Man ^{[6
,7
]}

Wang, Jiesi ^{[6
,7
]}

Liu, Hang ^{[1
,2
,3
]}

Yang, Ailing ^{[1
]}

Chen, Xi ^{[9
,10
]}

Liu, Jiazheng ^{[9
,10
]}

Winblad, Bengt ^{[4
,11
]}

Han, Hua ^{[9
,10
]}

Jiang, Tianzi ^{[8
]}

Wang, Weiwen ^{[6
,7
]}

Nilsson, Per ^{[4
]}

Guo, Wei ^{[1
,2
,3
]}

Lu, Bai ^{[1
,2
,3
]}

机构：

[1] Tsinghua Univ, Tsinghua Univ Peking Univ Joint Ctr Life Sci, Sch Pharmaceut Sci, IDG McGovern Inst Brain Res, Beijing, Peoples R China

[2] Res Inst Tsinghua Univ Shenzhen, R&D Ctr Diag & Treatment Major Brain Dis, Shenzhen, Guangdong, Peoples R China

[3] Capital Med Univ, Adv Innovat Ctr Human Brain Protect, Beijing Tiantan Hosp, Beijing, Peoples R China

[4] Karolinska Inst, Ctr Alzheimer Res, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden

[5] First Hosp Jilin Univ, Dept Otorhinolaryngol Head & Neck Surg, Changchun, Peoples R China

[6] Chinese Acad Sci, Inst Psychol, CAS Key Lab Mental Hlth, Beijing, Peoples R China

[7] Univ Chinese Acad Sci, Dept Psychol, Beijing, Peoples R China

[8] Chinese Acad Sci, Brainnetome Ctr, Inst Automat, Beijing, Peoples R China

[9] Univ CAS, Sch Future Technol, Res Ctr Brain Inspired Intelligence, Inst Automat,Natl Lab Pattern Recognit, Shanghai, Peoples R China

[10] Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligence Techn, Shanghai, Peoples R China

[11] Karolinska Univ Hosp, Theme Aging, Huddinge, Sweden

来源：

CELL RESEARCH | 2022年 / 32卷 / 02期

基金：

欧盟地平线“2020”; 中国国家自然科学基金; 瑞典研究理事会;

关键词：

AMYLOID-PRECURSOR-PROTEIN; TRANSGENIC MICE; MOUSE MODELS; SEX; ISOFORMS; MUTATION; MEMORY; AGE; NEURODEGENERATION; NEUROPATHOLOGY;

D O I：

10.1038/s41422-021-00582-x

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

A major obstacle in Alzheimer's disease (AD) research is the lack of predictive and translatable animal models that reflect disease progression and drug efficacy. Transgenic mice overexpressing amyloid precursor protein (App) gene manifest non-physiological and ectopic expression of APP and its fragments in the brain, which is not observed in AD patients. The App knock-in mice circumvented some of these problems, but they do not exhibit tau pathology and neuronal death. We have generated a rat model, with three familiar App mutations and humanized A beta sequence knocked into the rat App gene. Without altering the levels of full-length APP and other APP fragments, this model exhibits pathologies and disease progression resembling those in human patients: deposit of A beta plaques in relevant brain regions, microglia activation and gliosis, progressive synaptic degeneration and AD-relevant cognitive deficits. Interestingly, we have observed tau pathology, neuronal apoptosis and necroptosis and brain atrophy, phenotypes rarely seen in other APP models. This App knock-in rat model may serve as a useful tool for AD research, identifying new drug targets and biomarkers, and testing therapeutics.

引用

页码：157 / 175

页数：19

共 110 条

[1]

Abe Y, 2003, J NEUROSCI, V23, P8513

[2] Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention [J].