Authors: 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
Published: 2021-11-17
DOI: 10.1038/s41422-021-00582-x
Source: Full article
AbstractA 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. TheAppknock-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 familiarAppmutations and humanized Aβ sequence knocked into the ratAppgene. 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. ThisAppknock-in rat model may serve as a useful tool for AD research, identifying new drug targets and biomarkers, and testing therapeutics.