Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
Mol Neurobiol. 2022 Jul;59(7):4197-4208. doi: 10.1007/s12035-022-02843-1. Epub 2022 Apr 30.
Spinal cord injury (SCI) can result in significant neurological impairment and functional and cognitive deficits. It is well established that SCI results in focal neurodegeneration that gradually spreads to other cord areas. On the other hand, traumatic brain injury (TBI) is strongly associated with tau protein pathology and neurodegeneration that can spread in areas throughout the brain. Tau is a microtubule-associated protein abundant in neurons and whose abnormalities result in neuronal cell death. While SCI and TBI have been extensively studied, there is limited research on the relationship between SCI and brain tau pathology. As a result, in this study, we examined tau pathology in spinal cord and brain samples obtained from severe SCI mouse models at various time points. The effects of severe SCI on locomotor function, spatial memory, anxiety/risk-taking behavior were investigated. Immunostaining and immunoblotting confirmed a progressive increase in tau pathology in the spinal cord and brain areas. Moreover, we used electron microscopy to examine brain samples and observed disrupted mitochondria and microtubule structure following SCI. SCI resulted in motor dysfunction, memory impairment, and abnormal risk-taking behavior. Notably, eliminating pathogenic cis P-tau via systemic administration of appropriate monoclonal antibodies restored SCI's pathological and functional consequences. Thus, our findings suggest that SCI causes severe tauopathy that spreads to brain areas, indicating brain dysfunction. Additionally, tau immunotherapy with an anti-cis P-tau antibody could suppress pathogenic outcomes in SCI mouse models, with significant clinical implications for SCI patients. SCI induces profound pathogenic cis p-tau, which diffuses into the brain through CSF, resulting in brain neurodegeneration and cognitive decline.
脊髓损伤 (SCI) 可导致严重的神经功能障碍以及功能和认知缺陷。研究表明，SCI 会导致局灶性神经退行性病变，且这种病变会逐渐扩散到脊髓的其他区域。另一方面，创伤性脑损伤 (TBI) 与 Tau 蛋白病变和神经退行性病变密切相关，这些病变会在大脑的各个区域扩散。Tau 是一种富含神经元的微管相关蛋白，其异常会导致神经元细胞死亡。虽然 SCI 和 TBI 已经得到了广泛的研究，但关于 SCI 和大脑 Tau 病理学之间关系的研究却很有限。因此，在这项研究中，我们检查了严重 SCI 小鼠模型在不同时间点的脊髓和大脑样本中的 Tau 病理学。研究了严重 SCI 对运动功能、空间记忆、焦虑/冒险行为的影响。免疫染色和免疫印迹证实了 Tau 病理学在脊髓和大脑区域的逐渐增加。此外，我们使用电子显微镜检查了大脑样本，观察到 SCI 后线粒体和微管结构的破坏。SCI 导致运动功能障碍、记忆障碍和异常的冒险行为。值得注意的是，通过系统给予适当的单克隆抗体消除致病性 cis P-tau，可恢复 SCI 的病理和功能后果。因此，我们的研究结果表明，SCI 导致严重的 Tau 病，且 Tau 病会扩散到大脑区域，表明大脑功能障碍。此外，针对 cis P-tau 的 Tau 免疫疗法可以抑制 SCI 小鼠模型中的致病性结果，这对 SCI 患者具有重要的临床意义。SCI 会引起强烈的致病性 cis p-tau，其通过 CSF 扩散到大脑，导致大脑神经退行性病变和认知能力下降。
