A novel transgenic mouse line with hippocampus-dominant and inducible expression of truncated human tau.

IF 10.8 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration Pub Date : 2023-11-10 DOI:10.1186/s40035-023-00379-5

Yang Gao, Yuying Wang, Huiyang Lei, Zhendong Xu, Shihong Li, Haitao Yu, Jiazhao Xie, Zhentao Zhang, Gongping Liu, Yao Zhang, Jie Zheng, Jian-Zhi Wang

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引用次数: 0

Abstract

Background: Intraneuronal accumulation of hyperphosphorylated tau is a defining hallmark of Alzheimer's disease (AD). However, mouse models imitating AD-exclusive neuronal tau pathologies are lacking.

Methods: We generated a new tet-on transgenic mouse model expressing truncated human tau N1-368 (termed hTau368), a tau fragment increased in the brains of AD patients and aged mouse brains. Doxycycline (dox) was administered in drinking water to induce hTau368 expression. Immunostaining and Western blotting were performed to measure the tau level. RNA sequencing was performed to evaluate gene expression, and several behavioral tests were conducted to evaluate mouse cognitive functions, emotion and locomotion.

Results: Dox treatment for 1-2 months at a young age induced overt and reversible human tau accumulation in the brains of hTau368 transgenic mice, predominantly in the hippocampus. Meanwhile, the transgenic mice exhibited AD-like high level of tau phosphorylation, glial activation, loss of mature neurons, impaired hippocampal neurogenesis, synaptic degeneration and cognitive deficits.

Conclusions: This study developed a well-characterized and easy-to-use tool for the investigations and drug development for AD and other tauopathies.

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一种新的转基因小鼠系，具有截短的人tau的海马显性和诱导表达。

背景：神经元内过度磷酸化tau的积累是阿尔茨海默病（AD）的一个明确标志。然而，缺乏模拟AD专属神经元tau病理的小鼠模型。方法：我们产生了一种新的tet-on转基因小鼠模型，表达截短的人类tau N1-368（称为hTau368），一种在AD患者和老年小鼠大脑中增加的tau片段。在饮用水中施用多西环素（dox）以诱导hTau368的表达。进行免疫染色和蛋白质印迹以测量tau水平。进行RNA测序以评估基因表达，并进行多项行为测试以评估小鼠的认知功能、情绪和运动。结果：年轻时接受Dox治疗1-2个月，在hTau368转基因小鼠的大脑中诱导了明显且可逆的人类tau积累，主要在海马中。同时，转基因小鼠表现出AD样高水平的tau磷酸化、胶质细胞活化、成熟神经元丧失、海马神经发生受损、突触变性和认知缺陷。结论：本研究为AD和其他tau病的研究和药物开发开发开发了一种功能齐全、易于使用的工具。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Neurodegeneration Neuroscience-Cognitive Neuroscience

CiteScore

19.50

自引率

0.80%

发文量

审稿时长

10 weeks

期刊介绍： Translational Neurodegeneration, an open-access, peer-reviewed journal, addresses all aspects of neurodegenerative diseases. It serves as a prominent platform for research, therapeutics, and education, fostering discussions and insights across basic, translational, and clinical research domains. Covering Parkinson's disease, Alzheimer's disease, and other neurodegenerative conditions, it welcomes contributions on epidemiology, pathogenesis, diagnosis, prevention, drug development, rehabilitation, and drug delivery. Scientists, clinicians, and physician-scientists are encouraged to share their work in this specialized journal tailored to their fields.