Department of Neuropathology, Institute of Pathology, University Hospital, 4031 Basel, Switzerland.
Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9535-40. doi: 10.1073/pnas.1301175110. Epub 2013 May 20.
Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer's disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer's disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.
由过度磷酸化的 tau 形成的丝状包涵体是许多人类神经退行性疾病的特征，包括阿尔茨海默病、仅有缠结的痴呆、匹克病、嗜银颗粒病（AGD）、进行性核上性麻痹和皮质基底节变性。在阿尔茨海默病和 AGD 中，已经表明丝状 tau 似乎随着疾病的进展以刻板的方式传播。我们之前证明，从表达人类突变 P301S tau 的转基因小鼠的脑提取物注射到转基因表达野生型人类 tau 的小鼠（ALZ17 系）的脑中，导致野生型人类 tau 组装成纤维和 tau 包涵体从注射部位传播到解剖上相连的脑区。在这里，我们将来自患有各种 tau 病的人类死者的脑提取物注射到 ALZ17 小鼠的海马体和大脑皮层中。在所有情况下都形成了嗜银性 tau 包涵体，并且在注射相应的脑提取物后，我们再现了 AGD、PSP 和 CBD 的标志性病变。在将来自人类 tau 病的脑匀浆脑内注射到非转基因小鼠后，也形成了类似的包涵体。此外，tau 聚集物的诱导形成可以在小鼠脑中传播。这些发现表明，一旦 tau 聚集物在离散的脑区形成，它们就会自我传播并以类朊病毒样的方式传播。
