Traumatic brain injury (TBI) can lead to the development of chronic traumatic encephalopathy as a result of neuronal phosphorylated tau (p-tau) protein aggregation and neuroinflammation. Acid sphingomyelinase (Asm) may also contribute to post-TBI neurodegenerative disorders. We hypothesized that Asm inhibition would ameliorate p-tau aggregation, neuroinflammation, and behavioral changes after TBI in a murine model. TBI was generated using a weight-drop method. Asm inhibition in wild-type mice was achieved with a single injection of amitriptyline 1 h after TBI. Genetic Asm ablation was achieved using Asm-deficient mice (Asm^–/–). Thirty days after TBI, mice underwent behavioral testing with the forced swim test for symptoms of depression or were euthanized for neurohistological analysis. Neuroinflammation was quantified using the microglial markers, ionized calcium-binding adaptor molecule 1 and transmembrane protein 119. Compared to sham mice, TBI mice demonstrated increased hippocampal p-tau. Mice that received amitriptyline after TBI demonstrated decreased p-tau compared to mice that received a saline control. Further, post-TBI Asm^–/– mice demonstrated lower levels of p-tau compared to wild-type mice. Though a decrease in neuroinflammation was observed at 1 month post-TBI, no change was demonstrated with mice treated with amitriptyline. Similarly, TBI mice were more likely to show depression compared to mice that received amitriptyline after TBI. Utilizing a weight-drop method to induce moderate TBI, we have shown that genetic deficiency or pharmacological inhibition of Asm prevented hippocampal p-tau aggregation 1 month after injury as well as decreased symptoms of depression. These findings highlight an opportunity to potentially reduce the long-term consequences of TBI.

中文翻译：

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酸性鞘磷脂酶抑制可减轻创伤性脑损伤小鼠模型的组织病理学和行为变化。

由于神经元磷酸化 tau (p-tau) 蛋白聚集和神经炎症，创伤性脑损伤 (TBI) 可导致慢性创伤性脑病的发展。酸性鞘磷脂酶 (Asm) 也可能导致 TBI 后神经退行性疾病。我们假设 Asm 抑制会改善小鼠模型中 TBI 后的 p-tau 聚集、神经炎症和行为变化。TBI 是使用减重法生成的。TBI 后 1 小时单次注射阿米替林即可抑制野生型小鼠的 Asm。使用 Asm 缺陷小鼠 (Asm ^–/–）。TBI 后 30 天，小鼠接受了强迫游泳测试的行为测试，以确定抑郁症的症状，或者被安乐死以进行神经组织学分析。使用小胶质细胞标记物、离子钙结合接头分子 1 和跨膜蛋白 119 对神经炎症进行量化。与假小鼠相比，TBI 小鼠表现出海马 p-tau 增加。与接受盐水对照的小鼠相比，在 TBI 后接受阿米替林的小鼠表现出降低的 p-tau。此外，TBI 后 Asm ^–/–与野生型小鼠相比，小鼠表现出较低水平的 p-tau。虽然在 TBI 后 1 个月观察到神经炎症减少，但用阿米替林治疗的小鼠没有表现出任何变化。同样，与 TBI 后接受阿米替林的小鼠相比，TBI 小鼠更容易出现抑郁。利用减重方法诱导中度 TBI，我们已经证明，遗传缺陷或 Asm 的药理学抑制可防止损伤后 1 个月的海马 p-tau 聚集，并减轻抑郁症状。这些发现突出了潜在减少 TBI 长期后果的机会。