Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration
Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration
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DOI：
10.1523/jneurosci.0081-05.2005
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发表时间：
2005-04-06
影响因子：
5.3
通讯作者：
Trojanowski, JQ
中科院分区：
文献类型：
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作者：
Forman, MS;Lal, D;Trojanowski, JQ
神经元和神经胶质中的丝状tau包涵体是散发性和家族性tau蛋白病的神经病理学标志。由于tau基因突变是常染色体显性tau蛋白病“与17号染色体相关的额颞叶痴呆和帕金森综合征”的致病性，因此tau异常直接涉及疾病的发作和/或进展。虽然丝状tau聚集体被认为在导致神经元损失的变性机制中发挥作用，但神经胶质tau病理学对神经变性的贡献基本上仍未被探索。为了开始阐明神经胶质病理学在tau蛋白病中的作用，我们通过表达由神经胶质酸性蛋白（GFAP）启动子驱动的人tau蛋白来产生星形胶质细胞tau病理学的转基因（Tg）小鼠模型。而在对照小鼠的星形胶质细胞中未检测到内源性tau，在GFAP/tau Tg小鼠中，存在与GFAP网络的再分布相关的稳健的星形胶质细胞tau表达。随后，在星形胶质细胞中存在tau病理学的年龄依赖性积累，如在许多tau病变中观察到的，星形胶质细胞是Gallyas和硫代黄素S阳性的。这些Tg小鼠中的tau病理异常磷酸化、泛素化和丝状，并且这种病理的出现与不溶性tau蛋白的积累一致。此外，在具有强烈星形细胞tau病理学的区域中，存在轻度血脑屏障破坏、低分子量热休克蛋白的诱导和局灶性神经元变性。因此，这些Tg小鼠概括了在人tau蛋白病中观察到的星形胶质细胞病理学的关键特征，并证明了这种病理学的功能后果，包括在不存在神经元tau包涵体的情况下的神经元变性。
Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of sporadic and familial tauopathies. Because tau gene mutations are pathogenic for the autosomal dominant tauopathy "frontotemporal dementia and parkinsonism linked to chromosome 17," tau abnormalities are implicated directly in the onset and/or progression of disease. Although filamentous tau aggregates are acknowledged to play roles in degenerative mechanisms resulting in neuron loss, the contributions of glial tau pathology to neurodegeneration remain essentially unexplored. To begin to elucidate the role of glial pathology in tauopathies, we generated a transgenic (Tg) mouse model of astrocytic tau pathology by expressing the human tau protein driven by the glial fibrillary acidic protein (GFAP) promoter. Whereas endogenous tau was not detected in astrocytes of control mice, in GFAP/tau Tg mice there was robust astrocytic tau expression that was associated with a redistribution of the GFAP network. Subsequently, there was an age-dependent accumulation of tau pathology in astrocytes that was Gallyas and variably thioflavine S positive as observed in many tauopathies. The tau pathology in these Tg mice was abnormally phosphorylated, ubiquitinated, and filamentous, and the emergence of this pathology coincided with accumulation of insoluble tau protein. Furthermore, in regions with robust astrocytic tau pathology, there was mild blood-brain barrier disruption, induction of low-molecular-weight heat shock proteins, and focal neuron degeneration. Thus, these Tg mice recapitulate key features of astrocytic pathology observed in human tauopathies and demonstrate functional consequences of this pathology including neuron degeneration in the absence of neuronal tau inclusions.