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

• 作者: 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
• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2022,（2）
• 所属期刊栏目: ARTICLES
• 页码范围: 157-175
• 页数: 19页
• 语种: 英文

摘要

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.