International Experimental Central Nervous System Injury & Repair (IECNSIR), Dept. of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
Department of Neurology, Bethune International Peace Hospital, Zhongshan Road (West), Shijiazhuang, Hebei Province, P.R. China.
Int Rev Neurobiol. 2023;172:3-35. doi: 10.1016/bs.irn.2023.05.011. Epub 2023 Sep 26.
Hallmark of Alzheimer's disease include amyloid beta peptide and phosphorylated tau deposition in brain that could be aggravated following traumatic of concussive head injury. However, amyloid beta peptide or p-tau in spinal cord following injury is not well known. In this investigation we measured amyloid beta peptide and p-tau together with tumor necrosis factor-alpha (TNF-α) in spinal cord and brain following 48 h after spinal cord injury in relation to the blood-spinal cord and blood-brain barrier, edema formation, blood flow changes and cell injury in perifocal regions of the spinal cord and brain areas. A focal spinal cord injury was inflicted over the right dorsal horn of the T10-11 segment (4 mm long and 2 mm deep) and amyloid beta peptide and p-tau was measured in perifocal rostral (T9) and caudal (T12) spinal cord segments as well as in the brain areas. Our observations showed a significant increase in amyloid beta peptide in the T9 and T12 segments as well as in remote areas of brain and spinal cord after 24 and 48 h injury. This is associated with breakdown of the blood-spinal cord (BSCB) and brain barriers (BBB), edema formation, reduction in blood flow and cell injury. After 48 h of spinal cord injury elevation of amyloid beta peptide, phosphorylated tau (p-tau) and tumor necrosis factor-alpha (TNF-α) was seen in T9 and T12 segments of spinal cord in cerebral cortex, hippocampus and brain stem regions associated with microglial activation as seen by upregulation of Iba1 and CD86. Repeated nanowired delivery of cerebrolysin topically over the traumatized segment repeatedly together with monoclonal antibodies (mAb) to amyloid beta peptide (AβP), p-tau and TNF-α significantly attenuated amyloid beta peptide, p-tau deposition and reduces Iba1, CD68 and TNF-α levels in the brain and spinal cord along with blockade of BBB and BSCB, reduction in blood flow, edema formation and cell injury. These observations are the first to show that spinal cord injury induces Alzheimer's disease like symptoms in the CNS, not reported earlier.
阿尔茨海默病的特征包括大脑中淀粉样β肽和磷酸化 tau 的沉积，这些沉积可能会在创伤性或震荡性头部损伤后加重。然而，受伤后脊髓中的淀粉样β肽或 p-tau 尚不清楚。在这项研究中，我们测量了脊髓损伤后 48 小时内脊髓和大脑中的淀粉样β肽和 p-tau 以及肿瘤坏死因子-α（TNF-α），以了解与血脊髓和血脑屏障、水肿形成、血流变化和脊髓损伤周围区域以及大脑区域的细胞损伤有关的情况。在 T10-11 节段的右侧背角造成局灶性脊髓损伤（4 毫米长，2 毫米深），并测量了损伤周围的 T9 和 T12 脊髓节段以及大脑区域的淀粉样β肽和 p-tau。我们的观察结果显示，在损伤后 24 和 48 小时，T9 和 T12 节段以及大脑的远距离区域的淀粉样β肽显著增加。这与血脊髓（BSCB）和血脑屏障（BBB）的破裂、水肿形成、血流减少和细胞损伤有关。在脊髓损伤 48 小时后，T9 和 T12 脊髓节段、大脑皮质、海马体和脑干区域的淀粉样β肽、磷酸化 tau（p-tau）和肿瘤坏死因子-α（TNF-α）升高，这与小胶质细胞的激活有关，表现为 Iba1 和 CD86 的上调。重复经纳米线递送至创伤段的脑活素与针对淀粉样β肽（AβP）、p-tau 和 TNF-α 的单克隆抗体（mAb）联合使用可显著减轻淀粉样β肽、p-tau 沉积，并降低大脑和脊髓中的 Iba1、CD68 和 TNF-α 水平，同时阻断 BBB 和 BSCB、减少血流、水肿形成和细胞损伤。这些观察结果是首次表明脊髓损伤会在中枢神经系统中引起类似阿尔茨海默病的症状，这在以前的研究中尚未报道。
