Hall G F, Lee V M, Lee G, Yao J
Department of Biological Sciences, University of Massachusetts, Lowell 01854, USA.
Am J Pathol. 2001 Jan;158(1):235-46. doi: 10.1016/S0002-9440(10)63962-4.
The hyperphosphorylation of human tau and its aggregation into neurofibrillary tangles are central pathogenic events in familial tauopathies and Alzheimer's disease. However, the cellular consequences of neurofibrillary tangle formation in vivo have not been directly studied because cellular models of human neurofibrillary degeneration have been unavailable until recently. Incorporation of human tau into filaments in vivo and the association of filamentous tau with cytodegeneration were first demonstrated experimentally with the overexpression of human tau in identified neurons (anterior bulbar cells) in the lamprey central nervous system. In this system, filamentous tau deposits are associated with the loss of dendritic microtubules and synapses, plasma membrane degeneration, and eventually the formation of extracellular tau deposits and cell death. Here we show that human tau hyperphosphorylation in anterior bulbar cells is spatiotemporally correlated with a highly stereotyped sequence of degenerative stages closely resembling those seen in human neurofibrillary degeneration. Hyperphosphorylated tau deposits first appear in the distal dendrites and somata, together with degenerative changes that begin in distal dendrites and progress proximally over time. This sequence is independent of the tau isoform used, the presence of epitope tags and the method used to overexpress tau, and thus has important implications for the cytopathogenesis of human neurofibrillary disease.
人tau蛋白的过度磷酸化及其聚集成神经原纤维缠结是家族性tau蛋白病和阿尔茨海默病的核心致病事件。然而，由于直到最近才出现人类神经原纤维变性的细胞模型，因此尚未直接研究体内神经原纤维缠结形成的细胞后果。通过在七鳃鳗中枢神经系统中已确定的神经元（延髓前体细胞）中过表达人tau蛋白，首次通过实验证明了人tau蛋白在体内掺入细丝以及丝状tau蛋白与细胞变性的关联。在这个系统中，丝状tau蛋白沉积物与树突状微管和突触的丧失、质膜变性以及最终细胞外tau蛋白沉积物的形成和细胞死亡有关。在这里，我们表明延髓前体细胞中人tau蛋白的过度磷酸化在时空上与一系列高度刻板的退行性阶段相关，这些阶段与人类神经原纤维变性中所见的阶段非常相似。过度磷酸化的tau蛋白沉积物首先出现在远端树突和胞体中，同时伴随着始于远端树突并随时间向近端发展的退行性变化。这个序列与所使用的tau异构体、表位标签的存在以及用于过表达tau蛋白的方法无关，因此对人类神经原纤维疾病的细胞发病机制具有重要意义。
