创伤性脑损伤(TBI),特别是当中度到重度和重复性时,是几种进行性神经退行性疾病的强烈环境风险因素。已经报道了在TBI和TBI相关的神经退行性疾病中的反式反应DNA结合蛋白43(TDP-43)的错误定位和沉积。有人假设轴突病理学,TBI后的早期事件,可能促进TDP-43失调,并作为神经退行性过程的触发因素。我们试图确定阻断前变性Sarm1(无菌α和含有1个TIR基序)轴突死亡途径是否会减弱TBI后的TDP-43病理。我们对111个雄性Sarm1野生型,半合子,和敲除小鼠中度至重度重复性TBI(rTBI)使用先前建立的损伤范例。我们进行了连续的神经系统评估,然后进行了组织学分析(NeuN,MBP,Iba-1,GFAP,rTBI后1个月,pTDP-43和AT8)。Sarm1基因的遗传消融减弱了磷酸化TDP-43(pTDP-43)的表达和错位以及pTau的积累。此外,Sarm1基因敲除小鼠皮质神经元和轴突完整性显著改善,功能缺陷,并改善rTBI后的总生存率。相比之下,去除一个延迟的Sarm1等位基因,但并没有阻止,神经功能缺损和神经轴突丢失。然而,Sarm1单倍体不足的小鼠显示出较少的小胶质细胞增生,pTDP-43病理学,和与野生型小鼠相比时的pTau积累。这些数据表明,Sarm1介导的前变性途径有助于rTBI的发病机理,包括pTDP-43的病理性积累。这表明抗Sarm1疗法是在中度至重度rTBI后保持神经功能的可行方法。
Traumatic brain injury (TBI), particularly when moderate-to-severe and repetitive, is a strong environmental risk factor for several progressive neurodegenerative disorders. Mislocalization and deposition of transactive response DNA binding protein 43 (TDP-43) has been reported in both TBI and TBI-associated neurodegenerative diseases. It has been hypothesized that axonal pathology, an early event after TBI, may promote TDP-43 dysregulation and serve as a trigger for neurodegenerative processes. We sought to determine whether blocking the prodegenerative Sarm1 (sterile alpha and TIR motif containing 1) axon death pathway attenuates TDP-43 pathology after TBI. We subjected 111 male Sarm1 wild type, hemizygous, and knockout mice to moderate-to-severe repetitive TBI (rTBI) using a previously established injury paradigm. We conducted serial neurological assessments followed by histological analyses (NeuN, MBP, Iba-1, GFAP, pTDP-43, and AT8) at 1 month after rTBI. Genetic ablation of the Sarm1 gene attenuated the expression and mislocalization of phosphorylated TDP-43 (pTDP-43) and accumulation of pTau. In addition, Sarm1 knockout mice had significantly improved cortical neuronal and axonal integrity, functional deficits, and improved overall survival after rTBI. In contrast, removal of one Sarm1 allele delayed, but did not prevent, neurological deficits and neuroaxonal loss. Nevertheless, Sarm1 haploinsufficient mice showed significantly less microgliosis, pTDP-43 pathology, and pTau accumulation when compared to wild type mice. These data indicate that the Sarm1-mediated prodegenerative pathway contributes to pathogenesis in rTBI including the pathological accumulation of pTDP-43. This suggests that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after moderate-to-severe rTBI.