Traumatic brain injury (TBI) is associated in some studies with clinical dementia, and neuropathological features, including amyloid plaque deposition and Tau neurofibrillary degeneration commonly identified in Alzheimer's disease (AD). However, the molecular mechanisms linking TBI to AD remain unclear. Here we show that TBI activates transcription factor CCAAT/Enhancer Binding Protein Beta (C/EBPβ), increasing delta-secretase (AEP) expression. Activated AEP cleaves both APP and Tau at APP N585 and Tau N368 sites, respectively, which mediate AD pathogenesis by promoting Aβ production and Tau hyperphosphorylation and inducing neuroinflammation and neurotoxicity. Knockout of AEP or C/EBPβ diminishes TBI-induced AD-like pathology and cognitive impairment in the 3xTg AD mouse model. Remarkably, viral expression of AEP-resistant Tau N368A in the hippocampus of 3xTg mice also ameliorates the pathological and cognitive consequences of TBI. Finally, clinical TBI activates C/EBPβ and escalates AEP expression, leading to APP N585 and Tau N368 proteolytic cleavage in TBI patient brains. Hence, our findings support a potential role for AEP in linking TBI exposure with AD pathogenesis.

中文翻译：

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创伤性脑损伤通过 delta-secretase 触发 APP 和 Tau 裂解，介导阿尔茨海默病的病理学。

在一些研究中，创伤性脑损伤 (TBI) 与临床痴呆和神经病理学特征相关，包括在阿尔茨海默病 (AD) 中常见的淀粉样蛋白斑沉积和 Tau 神经原纤维变性。然而，将 TBI 与 AD 联系起来的分子机制仍不清楚。在这里，我们显示 TBI 激活转录因子 CCAAT/增强子结合蛋白 Beta (C/EBPβ)，增加 delta-secretase (AEP) 的表达。活化的 AEP 分别在 APP N585 和 Tau N368 位点切割 APP 和 Tau，这通过促进 Aβ 产生和 Tau 过度磷酸化以及诱导神经炎症和神经毒性来介导 AD 发病机制。在 3xTg AD 小鼠模型中，敲除 AEP 或 C/EBPβ 可减少 TBI 诱导的 AD 样病理学和认知障碍。值得注意的是，3xTg 小鼠海马中 AEP 抗性 Tau N368A 的病毒表达也改善了 TBI 的病理和认知后果。最后，临床 TBI 激活 C/EBPβ 并升高 AEP 表达，导致 TBI 患者大脑中的 APP N585 和 Tau N368 蛋白水解切割。因此，我们的研究结果支持 AEP 在将 TBI 暴露与 AD 发病机制联系起来的潜在作用。