Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Institute of Spinal and Spinal Cord Injury, Tongji University School of Medicine, Shanghai 200065, China.
Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China.
Prog Neurobiol. 2023 Aug;227:102467. doi: 10.1016/j.pneurobio.2023.102467. Epub 2023 May 29.
Spinal cord injury (SCI) leads to mental abnormalities such as dementia and depression; however, the molecular mechanism of SCI-induced dementia remains a matter of debate. Asparagine endopeptidase (AEP) mediated dementia by enhancing amyloid plaque and Tau hyperphosphorylation, indicating that it played an important role in neurodegeneration. Here we revealed that SCI stimulated AEP activation in mice with T9 contusion injury. Activated-AEP cleaved APP and Tau, resulting in APP C586 and Tau N368 formations, and consequentially accelerated Aβ deposit and Tau hyperphosphorylation, respectively. At 9 months following injury, mice demonstrated a severe deterioration in cognitive-behavioral function, which was corroborated by the presence of accumulated AD-specific pathologies. Surprisingly, activated AEP was found in the brains of mice with spinal cord injury. In contrast, AEP knockout reduced SCI-induced neuronal death and neuroinflammation, resulting in cognitive-behavioral restoration. Interestingly, compared to the full-length proteins, truncated Tau N368 and APP C586 were easier to bind to each other. These AEP-processed fragments can not only be induced to pre-formed fibrils, but also amplified their abilities of spreading and neurotoxicity in vitro. Furthermore, as a critical transcription factor of AEP, C/EBPβ was activated in injured spinal cord. Elevated C/EBPβ level, as well as microglia population and inflammatory cytokines were also noticed in the cortex and hippocampus of SCI mice. These neuroinflammation pathologies were close related to the amount of Tau N368 and APP C586 in brain. Moreover, administration with the AEP-specific inhibitor, compound #11, was shown to decelerate Aβ accumulation, tauopathy and C/EBPβ level in both spinal cord and brain of SCI mice. Thus, this study highlights the fact that spinal cord injury is a potential risk factor for dementia, as well as the possibility that C/EBPβ-AEP axis may play a role in SCI-induced cognitive impairment.
脊髓损伤（SCI）导致痴呆和抑郁等精神异常；然而，SCI 诱导痴呆的分子机制仍存在争议。天冬酰胺内肽酶（AEP）通过增强淀粉样斑块和 Tau 过度磷酸化介导痴呆，表明其在神经退行性变中起重要作用。在这里，我们揭示了 T9 挫伤损伤后 SCI 刺激小鼠 AEP 活化。活化的 AEP 切割 APP 和 Tau，导致 APP C586 和 Tau N368 的形成，分别加速 Aβ 沉积和 Tau 过度磷酸化。在损伤后 9 个月，小鼠表现出严重的认知行为功能恶化，这与 AD 特异性病理的积累相符。令人惊讶的是，在脊髓损伤的小鼠脑中发现了活化的 AEP。相比之下，AEP 敲除减少了 SCI 诱导的神经元死亡和神经炎症，导致认知行为恢复。有趣的是，与全长蛋白相比，截短的 Tau N368 和 APP C586 更容易相互结合。这些 AEP 处理的片段不仅可以诱导形成预纤维，而且还可以增强它们在体外的扩散和神经毒性能力。此外，作为 AEP 的关键转录因子，C/EBPβ在损伤的脊髓中被激活。在 SCI 小鼠的皮质和海马体中也观察到 C/EBPβ 水平升高，小胶质细胞群体和炎症细胞因子增加。这些神经炎症病理与脑中 Tau N368 和 APP C586 的量密切相关。此外，用 AEP 特异性抑制剂 #11 处理可减缓 SCI 小鼠脊髓和大脑中 Aβ 积累、tau 病变和 C/EBPβ 水平。因此，这项研究强调了脊髓损伤是痴呆的一个潜在危险因素，以及 C/EBPβ-AEP 轴在 SCI 诱导的认知障碍中可能发挥作用的可能性。
