Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice
Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice
复制标题
DOI：
10.2353/ajpath.2007.070345
复制
发表时间：
2007-09-01
影响因子：
6
通讯作者：
Brion, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Leroy, Karelle;Bretteville, Alexis;Brion, Jean-Pierre
以脑和脊髓受累为特征的神经退行性疾病通常显示tau聚集体的广泛积累。我们已经产生了一个转基因小鼠系（Tg30 tau）表达在前脑和脊髓的人tau蛋白轴承两个致病性突变（P301S和G272V）。这些小鼠出现年龄依赖性脑和海马萎缩、中枢和外周轴突病变、进行性运动障碍伴神经源性肌肉萎缩和神经纤维缠结，存活率降低。轴突球状体和轴突萎缩早于神经纤维缠结。neuronoproteary包涵体在3个月时在神经元中发育，并且有两种类型，表明神经元的选择性脆弱性形成不同类型的neuronoproteary聚集体。第一种类型的tau蛋白阳性神经元缠结，在前脑中更丰富，由带状19 nm宽的细丝和扭曲的成对螺旋细丝组成。第二种类型的tau蛋白和神经递质阳性神经元缠结在脊髓和脑干中更丰富，由10 nm宽的神经丝和19 nm直丝组成。无偏体视学分析表明，小鼠腰髓锥体神经元总数和神经元密度在12个月内没有减少。因此，该T930tau模型提供了轴突病先于缠结形成的证据，并且这两种病变都可以与选定脑区域中的明显神经元损失分离，而不是与神经元功能障碍分离。
Neurodegenerative diseases characterized by brain and spinal cord involvement often show widespread accumulations of tau aggregates. We have generated a transgenic mouse line (Tg30tau) expressing in the forebrain and the spinal cord a human tau protein bearing two pathogenic mutations (P301S and G272V). These mice developed age-dependent brain and hippocampal atrophy, central and peripheral axonopathy, progressive motor impairment with neurogenic muscle atrophy, and neurofibrillary tangles and had decreased survival. Axonal spheroids and axonal atrophy developed early before neurofibrillary tangles. Neurofibrillary inclusions developed in neurons at 3 months and were of two types, suggestive of a selective vulnerability of neurons to form different types of fibrillary aggregates. A first type of tau-positive neurofibrillary tangles, more abundant in the forebrain, were composed of ribbon-like 19-nm-wide -filaments and twisted paired helical filaments. A second type of tau and neurofilament-positive neurofibrillary tangles, more abundant in the spinal cord and the brainstem, were composed of 10-nm-wide neurofilaments and straight 19-nm filaments. Unbiased stereological analysis indicated that total number of pyramidal neurons and density of neurons in the lumbar spinal cord were not reduced up to 12 months in mice. This T930tau model thus provides evidence that axonopathy precedes tangle formation and that both lesions can be dissociated from overt neuronal loss in selected brain areas but not from neuronal dysfunction.