In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as 'mild' and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping - a novel functional neuroimaging technique - we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established.

中文翻译：

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轻度闭合性头部损伤对啮齿动物 tau 蛋白病和认知缺陷的影响：野生型和 rTg4510 小鼠的初步结果以及系统评价。


在人类中，大多数持续性创伤性脑损伤 (TBI) 被归类为“轻度”，并且最常见的是闭合性头部损伤 (CHI) 的结果。非穿透性 CHI 的影响不是良性的，可能会导致慢性病理和行为功能障碍，而反复的头部损伤可能会加剧这种情况。临床神经病理学相关研究提供的证据表明，tau 蛋白转化为异常磷酸化的蛋白毒性中间体 (p-tau) 可能是单次 TBI 引发并通过重复 TBI 增强的病理生理学的一部分。然而，啮齿动物中 p-tau 和 CHI 之间的联系仍然存在争议。为了通过实验解决这个问题，我们向 WT 或 rTg4510 小鼠诱导了一个或两个 CHI。我们发现 2× CHI 增加了 WT 小鼠和 rTg4510 小鼠的 tau 磷酸化。 WT 小鼠的行为特征发现 2× CHI 小鼠的径向臂水迷宫存在慢性缺陷，而这些缺陷在 1× CHI 小鼠中已部分解决。此外，使用带有 R1 映射的锰增强磁共振成像（一种新颖的功能性神经成像技术），我们发现与 1× CHI 相比，2× CHI 后 rTg4510 小鼠的缺陷更大。为了将我们的发现与该领域之前的工作结合起来，我们对啮齿类动物轻度重复 CHI 研究进行了系统回顾。遵循 Prisma 指南，我们确定了 25 篇经过同行评审的原创论文。我们的实验结果以及我们的系统综述提供了令人信服的证据，表明 tau 磷酸化通过实验性轻度 TBI 研究进行了修改；然而，p-tau 水平的变化并未得到普遍报道。 总之，我们的结果提供了证据，表明与单次 TBI 相比，重复 TBI 可能导致更严重和更持久的神经功能缺损，但无法确定恶化的结果与升高的 p-tau 之间的直接联系。