Lentiviral Delivery of the Human Wild-type Tau Protein Mediates a Slow and Progressive Neurodegenerative Tau Pathology in the Rat Brain
Lentiviral Delivery of the Human Wild-type Tau Protein Mediates a Slow and Progressive Neurodegenerative Tau Pathology in the Rat Brain
复制标题
DOI：
10.1038/mt.2013.66
复制
发表时间：
2013-07-01
影响因子：
12.4
通讯作者：
Colin, Morvane
中科院分区：
文献类型：
--
作者：
Caillierez, Raphaelle;Begard, Severine;Colin, Morvane
大多数Tau病模型使用Tau基因的突变形式MAPT，该基因在与17号染色体相关的帕金森病额颞叶痴呆（FTDP-17）中发现，并导致快速神经原纤维变性（NFD）。迄今为止，利用野生型（WT）人类Tau蛋白来模拟小鼠大脑中Tau蛋白的聚集和相关的神经退行性过程尚未成功。在本研究中，我们在大鼠海马中生成了一个原始的“散发性Tau样”模型，编码人类中发现的六种Tau亚型，使用慢病毒载体（lv）来传递人类WT Tau。人类WT Tau在锥体神经元中的过度表达导致NFD，其形态学特征和动力学反映了散发性Tau病中观察到的缓慢和散发性神经退行性过程，而不像FTDP-17突变体Tau P301L引发的快速神经退行性过程导致细胞死亡和鬼缠结。这个新模型强调了WT和突变型Tau诱导的病理过程背后的分子和细胞机制的差异，并表明在寻求理解散发性Tau病的过程中，应该优先考虑使用WT Tau的动物模型。
Most models for tauopathy use a mutated form of the Tau gene, MAPT, that is found in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) and that leads to rapid neurofibrillary degeneration (NFD). Use of a wild-type (WT) form of human Tau protein to model the aggregation and associated neurodegenerative processes of Tau in the mouse brain has thus far been unsuccessful. In the present study, we generated an original "sporadic tauopathy-like" model in the rat hippocampus, encoding six Tau isoforms as found in humans, using lentiviral vectors (LVs) for the delivery of a human WT Tau. The overexpression of human WT Tau in pyramidal neurons resulted in NFD, the morphological characteristics and kinetics of which reflected the slow and sporadic neurodegenerative processes observed in sporadic tauopathies, unlike the rapid neurodegenerative processes leading to cell death and ghost tangles triggered by the FTDP-17 mutant Tau P301L. This new model highlights differences in the molecular and cellular mechanisms underlying the pathological processes induced by WT and mutant Tau and suggests that preference should be given to animal models using WT Tau in the quest to understand sporadic tauopathies.