Impaired glutamate transport in a mouse model of tau pathology in astrocytes

被引:102
作者
Dabir, DV
Robinson, MB
Swanson, E
Zhang, B
Trojanowski, JQ
Lee, VMY
Forman, MS
机构
[1] Univ Penn, Dept Pathol Lab Med, Ctr Neurodegenerat Dis Res, Sch Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Childrens Hosp Philadelphia, Inst Aging, Sch Med, Philadelphia, PA 19104 USA
[3] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Sch Med, Philadelphia, PA 19104 USA
[4] Univ Penn, Dept Pharmacol, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA
关键词
tau protein; astrocytes; tauopathy; glutamate transporter; transgenic mice; neurodegenerative disease;
D O I
10.1523/JNEUROSCI.3861-05.2006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:644 / 654
页数:11
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