Volume 32, No 2, Feb 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 2, February 2022: 157-175   |  Open Access

ORIGINAL ARTICLES

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

Keliang Pang^1,2,3 , Richeng Jiang^4,5 , Wei Zhang⁶ , Zhengyi Yang⁷ , Lin-Lin Li⁸ , Makoto Shimozawa⁴ , Simone Tambaro⁴ , Johanna Mayer⁴ , Baogui Zhang⁷ , Man Li⁶ , Jiesi Wang⁶ , Hang Liu^1,2,3 , Ailing Yang¹ , Xi Chen⁸ , Jiazheng Liu⁸ , Bengt Winblad^4,9 , Hua Han⁸ , Tianzi Jiang⁷ , Weiwen Wang⁶ , Per Nilsson⁴ , Wei Guo^1,2,3,* , Bai Lu^1,2,3,*

¹School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing, China
²R&D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong, China
³Beijing Tiantan Hospital, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
⁴Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
⁵Department of Otorhinolaryngology Head and Neck Surgery, The First Hospital of Jilin University, Changchun, China
⁶CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, and Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
⁷Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, China
⁸Research Center for Brain-inspired Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, School of Future Technology, University of CAS, and CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
⁹Theme Aging, Karolinska University Hospital, Huddinge, Sweden
Correspondence: Wei Guo(wguo@tsinghua.edu.cn)Bai Lu(bai_lu@tsinghua.edu.cn)

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 Aβ 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 Aβ 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.

https://doi.org/10.1038/s41422-021-00582-x

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