Spinal cord injury-activated C/EBPβ-AEP axis mediates cognitive impairment through APP C586/Tau N368 fragments spreading

作者：Zhourui Wu, Ran Zhu, Yan Yu, Jianjie Wang, Xiao Hu, Wei Xu, Yilong Ren, Chen Li, Zhili Zeng, Bin Ma, Ning Xie, Gufa Lin, Bei Ma, Rongrong Zhu, Keqiang Ye, Liming Cheng · 发表于：Progress in Neurobiology · 年份：2023 · DOI：10.1016/j.pneurobio.2023.102467 · 被引用次数：19 · 研究领域：Peptidase Inhibition and Analysis、Signaling Pathways in Disease、Neuropeptides and Animal Physiology

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 hippoca...