A major obstacle in Alzheimer's disease (AD) research is the lackof 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.

Keliang Pang;Richeng Jiang;Wei Zhang;Zhengyi Yang;Lin-Lin Li;Makoto Shimozawa;Simone Tambaro;Johanna Mayer;Baogui Zhang;Man Li;Jiesi Wang;Hang Liu;Ailing Yang;Xi Chen;Jiazheng Liu;Bengt Winblad;Hua Han;Tianzi Jiang;Weiwen Wang;Per Nilsson;Wei Guo;Bai Lu

School of Pharmaceutical Sciences,IDG/McGovern Institute for Brain Research,Tsinghua University-Peking University Joint Center for Life Sciences,Tsinghua University,Beijing,China;R&D Center for the Diagnosis and Treatment of Major Brain Diseases,Research Institute of Tsinghua University in Shenzhen,Shenzhen,Guangdong,China;Beijing Tiantan Hospital,Advanced Innovation Center for Human Brain Protection,Capital Medical University,Beijing,China;Department of Neurobiology,Care Sciences and Society,Division of Neurogeriatrics,Center for Alzheimer Research,Karolinska Institutet,Stockholm,Sweden;Department of Otorhinolaryngology Head and Neck Surgery,The First Hospital of Jilin University,Changchun,China;CAS Key Laboratory of Mental Health,Institute of Psychology,Chinese Academy of Sciences,and Department of Psychology,University of Chinese Academy of Sciences,Beijing,China;Brainnetome Center,Institute of Automation,Chinese Academy of Sciences,Beijing,China;Research 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;Theme Aging,Karolinska University Hospital,Huddinge,Sweden

细胞研究（英文版）

[1]Keliang Pang;Richeng Jiang;Wei Zhang;Zhengyi Yang;Lin-Lin Li;Makoto Shimozawa;Simone Tambaro;Johanna Mayer;Baogui Zhang;Man Li;Jiesi Wang;Hang Liu;Ailing Yang;Xi Chen;Jiazheng Liu;Bengt Winblad;Hua Han;Tianzi Jiang;Weiwen Wang;Per Nilsson;Wei Guo;Bai Lu-.An App knock-in rat model for Alzheimer's disease exhibiting Aβ and tau pathologies,neuronal death and cognitive impairments)[J].细胞研究（英文版）,2022(02):157-175

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