GFP-Mutant Human Tau Transgenic Mice Develop Tauopathy Following CNS Injections of Alzheimer's Brain-Derived Pathological Tau or Synthetic Mutant Human Tau Fibrils
GFP-Mutant Human Tau Transgenic Mice Develop Tauopathy Following CNS Injections of Alzheimer's Brain-Derived Pathological Tau or Synthetic Mutant Human Tau Fibrils
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DOI：
10.1523/jneurosci.2393-17.2017
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发表时间：
2017-11-22
影响因子：
5.3
通讯作者：
Lee, Virginia M. -Y.
中科院分区：
文献类型：
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作者：
Gibbons, Garrett S.;Banks, Rachel A.;Lee, Virginia M. -Y.
以tau蛋白的细胞内聚集为特征的神经变性蛋白质病（称为tau病）包括阿尔茨海默病（AD）、具有tau病理的额颞叶变性（FTLD）（FTLD-tau）和相关病症。来源于人AD脑的病理性tau蛋白（AD-tau）充当蛋白质病种子，其在脑内注射到tau转基因（Tg）和野生型小鼠中后引发可溶性tau的模板化聚集，从而模拟人tau病理。在这项研究中，我们发现，表达人类tau蛋白的两种性别的老年Tg小鼠（T40 PL-GFP Tg小鼠系）具有绿色荧光蛋白标记的致病性P301 L MAPT突变，表现出过度磷酸化的tau错误定位到神经元的体细胞树突结构域，但这些小鼠没有发展从头不溶性tau聚集体，这是人类AD和相关tau蛋白病的特征。然而，脑内注射T40 PL预形成的原纤维（PFF）或AD-tau种子到T40 PL-GFP小鼠诱导了大量的过度磷酸化的T40 PL-GFP的神经元内病理性包涵体。这些病理性tau的注射导致tau病理从注射部位传播到神经解剖学连接的脑区域，并且这些tau内含物由T40 PL-GFP和WT内源性小鼠tau组成。从新生T40 PL-GFP小鼠的脑培养的原代神经元提供了用于检查tau PFF的摄取和定位的信息性体外模型。这些发现证明了T40 PL-GFP在体内通过合成PFF和人AD-tau的接种聚集以及该系统用于研究tau聚集体的神经病理学扩散的效用。
Neurodegenerative proteinopathies characterized by intracellular aggregates of tau proteins, termed tauopathies, include Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau), and related disorders. Pathological tau proteins derived from human AD brains (AD-tau) act as proteopathic seeds that initiate the templated aggregation of soluble tau upon intracerebral injection into tau transgenic (Tg) and wild-type mice, thereby modeling human tau pathology. In this study, we found that aged Tg mice of both sexes expressing human tau proteins harboring a pathogenic P301L MAPT mutation labeled with green fluorescent protein (T40PL-GFP Tg mouse line) exhibited hyperphosphorylated tau mislocalized to the somatodentritic domain of neurons, but these mice did not develop de novo insoluble tau aggregates, which are characteristic of human AD and related tauopathies. However, intracerebral injections of either T40PL preformed fibrils (PFFs) or AD-tau seeds into T40PL-GFP mice induced abundant intraneuronal pathological inclusions of hyperphosphorylated T40PL-GFP. These injections of pathological tau resulted in the propagation of tau pathology from the injection site to neuroanatomically connected brain regions, and these tau inclusions consisted of both T40PL-GFP and WT endogenous mouse tau. Primary neurons cultured from the brains of neonatal T40PL-GFP mice provided an informative in vitro model for examining the uptake and localization of tau PFFs. These findings demonstrate the seeded aggregation of T40PL-GFP in vivo by synthetic PFFs and human AD-tau and the utility of this system to study the neuropathological spread of tau aggregates.