One of the consistent pathologies associated with both clinical and experimental traumatic brain injury is axonal injury, especially following mild traumatic brain injury (or concussive injury). Several lines of experimental evidence have demonstrated a role for NAD+ metabolism in axonal degeneration. One of the enzymes that metabolizes NAD+ in axons is Sarm1 (Sterile Alpha and TIR Motif Containing 1), and its activity is thought to play a key role in axonal degeneration. Using a Sarm1 knock-out mouse, we examined if loss of Sarm1 offers axonal injury protection and improves cognitive outcome after repeated mild closed head injury (rmCHI). Our results indicate that rmCHI caused white matter damage that can be observed in the corpus callosum, cingulum bundle, alveus of the hippocampus, and fimbria of the fornix of wild-type mice. These pathological changes were markedly reduced in injured Sarm1-/- mice. Interestingly, the activation of astrocytes and microglia was also attenuated in the areas with white matter damage, suggesting reduced inflammation. Associated with these improved pathological outcomes, injured Sarm1-/- mice performed significantly better in both motor and cognitive tasks. Taken together, our results suggest that strategies aimed at inhibiting Sarm1 and/or restoring NAD+ levels in injured axons may have therapeutic utility.

中文翻译：

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Sarm1 丢失减少了轴突损伤并改善了重复性轻度闭合性头部损伤后的认知结果。

与临床和实验性脑外伤相关的一致病理之一是轴突损伤，尤其是在轻度外伤性脑损伤（或脑震荡）之后。几条实验证据表明 NAD+ 代谢在轴突变性中起作用。在轴突中代谢 NAD+ 的酶之一是 Sarm1（Sterile Alpha 和 TIR Motif Containing 1），其活性被认为在轴突变性中起关键作用。使用 Sarm1 敲除小鼠，我们检查了 Sarm1 的缺失是否提供轴突损伤保护并改善重复轻度闭合性头部损伤 (rmCHI) 后的认知结果。我们的结果表明 rmCHI 引起了白质损伤，可以在野生型小鼠的胼胝体、扣带束、海马齿槽和穹窿伞毛中观察到白质损伤。在受伤的 Sarm1-/- 小鼠中，这些病理变化显着减少。有趣的是，星形胶质细胞和小胶质细胞的激活在白质损伤区域也减弱，表明炎症减轻。与这些改善的病理结果相关，受伤的 Sarm1-/- 小鼠在运动和认知任务中表现得更好。总之，我们的结果表明，旨在抑制 Sarm1 和/或恢复受损轴突中 NAD+ 水平的策略可能具有治疗效用。受伤的 Sarm1-/- 小鼠在运动和认知任务中表现明显更好。总之，我们的结果表明，旨在抑制 Sarm1 和/或恢复受损轴突中 NAD+ 水平的策略可能具有治疗效用。受伤的 Sarm1-/- 小鼠在运动和认知任务中表现明显更好。总之，我们的结果表明，旨在抑制 Sarm1 和/或恢复受损轴突中 NAD+ 水平的策略可能具有治疗效用。