First transgenic rat model developing progressive cortical neurofibrillary tangles
First transgenic rat model developing progressive cortical neurofibrillary tangles
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DOI：
10.1016/j.neurobiolaging.2010.10.015
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发表时间：
2012-07-01
影响因子：
4.2
通讯作者：
Novak, Michal
中科院分区：
文献类型：
--
作者：
Filipcik, Peter;Zilka, Norbert;Novak, Michal
由错误折叠的tau蛋白引起的神经原纤维变性被认为是阿尔茨海默病(AD)的重要病理特征之一。在本研究中，我们介绍了一种新的转基因大鼠模型，该模型表达了人截短的tau，它包括3个微管结合结构域(3R)和一个富含Pro的区域(3R tau151-391)。转基因大鼠的大脑皮质区域发生了进行性的年龄依赖性神经纤维变性。神经原纤维缠结(NFTs)满足用于鉴定人类阿尔茨海默病神经原纤维变性的几个关键组织学标准，包括嗜银、刚果红双折射和硫代黄素S反应。神经原纤维缠结也被用于检测人脑中病理tau的抗体，包括DC11，识别异常的tau构象和针对tau蛋白过度磷酸化形式的抗体。此外，神经原纤维变性的特征是广泛形成由大鼠内源性和截短的tau物种组成的肌糖不溶性tau蛋白复合体。有趣的是，转基因大鼠的大脑皮层和海马区都没有显示出神经元的丢失。我们认为，新的转基因大鼠人类变态反应模型是针对阿尔茨海默型神经纤维变性的临床前药物开发的有价值的工具。(C)2012 Elsevier Inc.保留所有权利。
Neurofibrillary degeneration induced by misfolded protein tau is considered to be one of the key pathological hallmarks of Alzheimer's disease (AD). In the present study, we have introduced a novel transgenic rat model expressing a human truncated tau that encompasses 3 microtubule binding domains (3R) and a proline-rich region (3R tau151-391). The transgenic rats developed progressive age-dependent neurofibrillary degeneration in the cortical brain areas. Neurofibrillary tangles (NFTs) satisfied several key histological criteria used to identify neurofibrillary degeneration in human Alzheimer's disease including argyrophilia, Congo red birefringence, and Thioflavin S reactivity. Neurofibrillary tangles were also identified with antibodies used to detect pathologic tau in the human brain, including DC11, recognizing an abnormal tau conformation and antibodies that are specific for hyperphosphorylated forms of tau protein. Moreover, neurofibrillary degeneration was characterized by extensive formation of sarkosyl insoluble tau protein complexes consisting of rat endogenous and truncated tau species. Interestingly, the transgenic rats did not show neuronal loss either in the cortex or in the hippocampus. We suggest that novel transgenic rat model for human tauopathy represents a valuable tool in preclinical drug discovery targeting neurofibrillary degeneration of Alzheimer's type. (C) 2012 Elsevier Inc. All rights reserved.