Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Neurobiol Dis. 2021 Jun;153:105330. doi: 10.1016/j.nbd.2021.105330. Epub 2021 Mar 10.
Traumatic brain injury (TBI) is associated with widespread tau pathology in about 30% of patients surviving late after injury. We previously found that TBI in mice induces the formation of an abnormal form of tau (tau) which progressively spreads from the site of injury to remote brain regions. Intracerebral inoculation of TBI brain homogenates into naïve mice induced progressive tau pathology, synaptic loss and late cognitive decline, suggesting a pivotal role of tau in post-TBI neurodegeneration. However, the possibility that tau was a marker of TBI-associated neurodegeneration rather than a toxic driver of functional decline could not be excluded. Here we employed the nematode C. elegans as a biosensor to test the pathogenic role of TBI generated tau. The motility of this nematode depends on efficient neuromuscular transmission and is exceptionally sensitive to the toxicity of amyloidogenic proteins, providing a tractable model for our tests. We found that worms exposed to brain homogenates from chronic but not acute TBI mice, or from mice in which tau had been transmitted by intracerebral inoculation, had impaired motility and neuromuscular synaptic transmission. Results were similar when worms were given brain homogenates from transgenic mice overexpressing tau P301L, a tauopathy mouse model, suggesting that TBI-induced and mutant tau have similar toxic properties. P301L brain homogenate toxicity was similar in wild-type and ptl-1 knock-out worms, indicating that the nematode tau homolog protein PTL-1 was not required to mediate the toxic effect. Harsh protease digestion to eliminate the protein component of the homogenates, pre-incubation with anti-tau antibodies or tau depletion by immunoprecipitation, abolished the toxicity. Homogenates of chronic TBI brains from tau knock-out mice were not toxic to C. elegans, whereas oligomeric recombinant tau was sufficient to impair their motility. This study indicates that tau impairs motor activity and synaptic transmission in C. elegans and supports a pathogenic role of tau in the long-term consequences of TBI. It also sets the groundwork for the development of a C. elegans-based platform for screening anti-tau compounds.
创伤性脑损伤（TBI）与大约 30%的幸存者在受伤后晚期的广泛 tau 病理学有关。我们之前发现，小鼠的 TBI 会诱导 tau（tau）形成一种异常形式，这种异常形式会从损伤部位逐渐扩散到大脑的远处区域。将 TBI 脑匀浆颅内接种到天真小鼠中会诱导渐进性 tau 病理学、突触丧失和晚期认知能力下降，表明 tau 在创伤后神经退行性变中起着关键作用。然而，tau 是 TBI 相关神经退行性变的标志物而不是功能下降的毒性驱动因素的可能性不能被排除。在这里，我们利用线虫 C. elegans 作为生物传感器来测试 TBI 产生的 tau 的致病作用。这种线虫的运动能力取决于有效的神经肌肉传递，对线粒体蛋白的毒性极其敏感，为我们的测试提供了一个可行的模型。我们发现，暴露于慢性而非急性 TBI 小鼠的脑匀浆或通过颅内接种传递 tau 的小鼠的脑匀浆的线虫运动能力受损，神经肌肉突触传递受损。当线虫给予过表达 tau P301L 的转基因小鼠的脑匀浆时，结果相似，tauopathy 小鼠模型，表明 TBI 诱导的和突变的 tau 具有相似的毒性特性。在野生型和 ptl-1 敲除线虫中，P301L 脑匀浆毒性相似，表明线虫 tau 同源蛋白 PTL-1 不是介导毒性作用所必需的。剧烈的蛋白酶消化以消除匀浆的蛋白质成分，预孵育抗 tau 抗体或免疫沉淀耗竭 tau，可以消除毒性。tau 敲除小鼠的慢性 TBI 脑匀浆对 C. elegans 没有毒性，而寡聚重组 tau 足以损害它们的运动能力。这项研究表明，tau 会损害 C. elegans 的运动活性和突触传递，并支持 tau 在 TBI 长期后果中的致病作用。它还为基于 C. elegans 的筛选抗 tau 化合物的平台的开发奠定了基础。
