An App knock-in rat model for Alzheimer\u2019s disease exhibiting A\u03b2 and tau pathologies, neuronal death and cognitive impairments

Keliang Pang,Jiazheng Liu,Baogui Zhang,Man Li,Huan Liu ,Bengt Winblad,Tianzi Jiang,Linlin Li ,Per Nilsson,Yang Ai ,Weiwen Wang,Zhengyi Yang,Wei Guo,Hua Han,Johanna Mayer,Jiesi Wang,Wei Zhang,Xi Chen,Simone Tambaro,Makoto Shimozawa,Richeng Jiang,Bai Lu

doi:10.1038/s41422-021-00582-x

Abstract

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.

Highlights

IntroductionAlzheimer’s disease (AD) has brought the heaviest social burden to the modern aging society.[1,2] The pathological hallmarks for AD include amyloid β peptide (Aβ)-containing senile plaques, tau-containing neurofibrillary tangles, progressive neuronal death, and neuroinflammation.[2] As such, amyloid and tau cascade hypotheses have been proposed to explain AD pathogenesis.[3,4,5] Despite the progress in understanding some of the pathogenic mechanisms, efforts in developing disease-modifying therapies for AD have so far been unsuccessful.[6,7]
Alzheimer’s disease (AD) is one of the most prominent age-related diseases and the major cause of elderly disability, with progressive impairments in memory, personality, and other cognitive functions.AD has brought the heaviest social burden to the modern aging society.[1,2] The pathological hallmarks for AD include amyloid β peptide (Aβ)-containing senile plaques, tau-containing neurofibrillary tangles, progressive neuronal death, and neuroinflammation.[2]
The Aβ sequence was humanized by appears that in the three brain areas examined, Aβ deposits introducing mutations leading to the substitutions G676R, F681Y, progress more rapidly in females than males, especially after and R684H

Summary

Introduction

AD has brought the heaviest social burden to the modern aging society.[1,2] The pathological hallmarks for AD include amyloid β peptide (Aβ)-containing senile plaques, tau-containing neurofibrillary tangles, progressive neuronal death, and neuroinflammation.[2] As such, amyloid and tau cascade hypotheses have been proposed to explain AD pathogenesis.[3,4,5] Despite the progress in understanding some of the pathogenic mechanisms, efforts in developing disease-modifying therapies for AD have so far been unsuccessful.[6,7]. Many factors may have contributed to this but one of the major hurdles appears to be the shortage of animal models that fully recapitulate the disease pathogenesis and are useful for testing experimental drugs.[8,9,10,11] Over decades hundreds of models have been developed, but few could genuinely reproduce the major neuropathologic phenotypes seen in AD patients.[9,10,11] This may have contributed to the fact that quite a few candidate AD drugs shown to be effective in AD animal models have failed in clinical trials.[11]

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Conclusion