Transmission and spreading of tauopathy in transgenic mouse brain
Transmission and spreading of tauopathy in transgenic mouse brain
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DOI：
10.1038/ncb1901
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发表时间：
2009-07-01
影响因子：
21.3
通讯作者：
Tolnay, Markus
中科院分区：
文献类型：
--
作者：
Clavaguera, Florence;Bolmont, Tristan;Tolnay, Markus
过度磷酸化的tau组成了几种神经退行性疾病的丝状细胞内包涵体，包括阿尔茨海默病(1)。在疾病过程中，神经元tau包涵体首先出现在经嗅觉皮质，从那里它们似乎扩散到海马结构和新皮质[2]。当包涵体到达海马体时，认知障碍变得明显，丰富的新皮质tau包涵体和细胞外β-淀粉样蛋白沉积是阿尔茨海默病的明确病理特征。在没有β-淀粉样蛋白沉积的情况下，大量的tau包涵体定义了Pick病、进行性核上性麻痹、皮质基底膜变性和其他疾病(1)。Tau突变导致家族性额颞叶痴呆，确立tau蛋白功能障碍足以导致神经变性和痴呆(3-5)。因此，在神经细胞中表达突变型(例如P301S)人tau的转基因小鼠表现出tau病的基本特征，包括神经变性和由过度磷酸化的tau蛋白(6，8)组成的丰富的细丝。相比之下，表达野生型人tau单亚型的小鼠品系不会产生tau丝或表现出神经退化(7，8)。在这里，我们使用tau表达系来研究实验性tau病是否可以传播。我们发现，将突变型P301S tau表达小鼠的脑提取液注射到转基因野生型tau表达动物的大脑中，可以诱导野生型人tau组装成细丝，并将病理从注射部位传播到邻近的脑区。
Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease(1). In the disease process, neuronal tau inclusions first appear in the transentorhinal cortex from where they seem to spread to the hippocampal formation and neocortex(2). Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular beta-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. An abundance of tau inclusions, in the absence of beta-amyloid deposits, defines Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases(1). Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia(3-5). Thus, transgenic mice expressing mutant (for example, P301S) human tau in nerve cells show the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein(6,8). By contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or show neurodegeneration(7,8). Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces assembly of wild-type human tau into filaments and spreading of pathology from the site of injection to neighbouring brain regions.