Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein
Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein
复制标题
DOI：
10.1038/78078
复制
发表时间：
2000-08-01
期刊：
影响因子：
30.8
通讯作者：
Hutton, M
中科院分区：
文献类型：
--
作者：
Lewis, J;McGowan, E;Hutton, M
由微管相关蛋白 tau 组成的神经原纤维缠结 (NFT) 在阿尔茨海默病 (AD)、皮克病、进行性核上性麻痹 (PSP) 和皮质基底节变性 (1) (CBD) 中很常见。编码 tau 蛋白的基因 (Mtapt) 突变会导致与 17 号染色体 (FTDP-17) 相关的额颞叶痴呆和帕金森病。从而证明tau蛋白功能障碍可直接导致神经退行性变(2)。含有最常见的 (3-5) FTDP-17 突变 (P301L) 的人类 tau 表达会导致转基因小鼠出现运动和行为缺陷，并且 NFT 的发展具有年龄和基因剂量依赖性。这种表型早在半合子动物中 6.5 个月时就出现，在纯合子动物中早在 4.5 个月时就出现了。 NFT 和 Pick-body 样神经元病变发生在杏仁核、间隔核、视前核、下丘脑、中脑、笔、髓质、小脑深部核和脊髓，在皮质、海马和基底神经节中出现 tau 免疫反应性前缠结。 NFT 最多的区域有反应性神经胶质增生。脊髓存在轴突球体、前角细胞折腾和前脊髓根轴突变性。我们还看到了周围神经病变和骨骼肌神经源性萎缩。大脑和脊髓含有不溶性 tau 蛋白，它们与 AD 和 FTDP-17 大脑中的不溶性 tau 蛋白共同迁移。表达 P301L 突变 tau 蛋白的小鼠表型模仿了人类 tau 蛋白病的特征，并为研究 NFT 疾病的发病机制提供了模型。
Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration(1) (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). thereby proving that tau dysfunction can directly result in neurodegeneration(2). Expression of human tau containing the most common(3-5) FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pens, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell toss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.