Dabir Deepa V, Robinson Michael B, Swanson Eric, Zhang Bin, Trojanowski John Q, Lee Virginia M-Y, Forman Mark S
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Neurosci. 2006 Jan 11;26(2):644-54. doi: 10.1523/JNEUROSCI.3861-05.2006.
Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of tauopathies. The discovery of microtubule-associated protein tau gene mutations that are pathogenic for a heterogenous group of neurodegenerative disorders, called frontotemporal dementia and parkinsonism linked to chromosome-17 (FTDP-17), directly implicate tau abnormalities in the onset/progression of disease. Although the role of tau pathology in neurons in disease pathogenesis is well accepted, the contribution of glial pathology is essentially unknown. We recently generated a transgenic (Tg) mouse model of tau pathology in astrocytes by expressing the human tau protein under the control of the glial fibrillary acidic protein (GFAP) promoter. Both wild-type and FTDP-17 mutant GFAP/tau Tg animals manifest an age-dependent accumulation of tau inclusions in astrocytes that resembles the pathology observed in human tauopathies. We further demonstrate that both strains of Tg mice manifest compromised motor function that correlates with altered expression of the glial glutamate-aspartate transporter and occurs before the development of tau pathology. Subsequently, the Tg mice manifest additional deficits in neuromuscular strength that correlates with reduced expression of glutamate transporter-1 (GLT-1) and occurs concurrent with tau inclusion pathology. Reduced GLT-1 expression was associated with a progressive decrease in sodium-dependent glutamate transport capacity. Reductions in GLT-1 expression were also observed in corticobasal degeneration, a tauopathy with prominent pathology in astrocytes. Less robust changes were observed in Alzheimer's disease in which neuronal tau pathology predominates. Thus, these Tg mice recapitulate features of astrocytic pathology observed in tauopathies and implicate a role for altered astrocyte function in the pathogenesis of these disorders.
神经元和胶质细胞中的丝状tau包涵体是tau蛋白病的神经病理学标志。微管相关蛋白tau基因突变的发现，这些突变对一组异质性神经退行性疾病具有致病性，称为与17号染色体相关的额颞叶痴呆和帕金森综合征（FTDP-17），直接表明tau异常与疾病的发生/进展有关。尽管tau病理学在神经元疾病发病机制中的作用已被广泛接受，但胶质细胞病理学的作用基本上尚不清楚。我们最近通过在胶质纤维酸性蛋白（GFAP）启动子的控制下表达人tau蛋白，建立了星形胶质细胞中tau病理学的转基因（Tg）小鼠模型。野生型和FTDP-17突变型GFAP/tau Tg动物均表现出星形胶质细胞中tau包涵体的年龄依赖性积累，这类似于在人类tau蛋白病中观察到的病理学特征。我们进一步证明，两种Tg小鼠品系均表现出运动功能受损，这与胶质谷氨酸-天冬氨酸转运体表达的改变相关，且发生在tau病理学发展之前。随后，Tg小鼠在神经肌肉力量方面表现出额外的缺陷，这与谷氨酸转运体-1（GLT-1）表达的降低相关，且与tau包涵体病理学同时发生。GLT-1表达降低与钠依赖性谷氨酸转运能力的逐渐下降有关。在皮质基底节变性中也观察到GLT-1表达降低，这是一种在星形胶质细胞中具有突出病理学特征的tau蛋白病。在以神经元tau病理学为主的阿尔茨海默病中观察到的变化则不那么明显。因此，这些Tg小鼠概括了在tau蛋白病中观察到的星形胶质细胞病理学特征，并暗示星形胶质细胞功能改变在这些疾病发病机制中的作用。
