Traumatic brain injury (TBI) has been recognized as an important risk factor for Alzheimer’s disease (AD). However, the molecular mechanisms by which TBI contributes to developing AD remain unclear. Here, we provide evidence that aberrant production of TDP-43 is a key factor in promoting AD neuropathology and synaptic and cognitive deterioration in mouse models of mild closed head injury (CHI). We observed that a single mild CHI is sufficient to exacerbate AD neuropathology and accelerate synaptic and cognitive deterioration in APP transgenic mice but repeated mild CHI are required to induce neuropathological changes and impairments in synaptic plasticity, spatial learning, and memory retention in wild-type animals. Importantly, these changes in animals exposed to a single or repeated mild CHI are alleviated by silencing of TDP-43 but reverted by rescue of the TDP-43 knockdown. Moreover, overexpression of TDP-43 in the hippocampus aggravates AD neuropathology and provokes cognitive impairment in APP transgenic mice, mimicking single mild CHI-induced changes. We further discovered that neuroinflammation triggered by TBI promotes NF-κB-mediated transcription and expression of TDP-43, which in turn stimulates tau phosphorylation and Aβ formation. Our findings suggest that excessive production of TDP-43 plays an important role in exacerbating AD neuropathology and in driving synaptic and cognitive declines following TBI.

创伤性脑损伤（TBI）已被认为是阿尔茨海默病（AD）的重要危险因素。然而，TBI 导致 AD 发生的分子机制仍不清楚。在这里，我们提供的证据表明，TDP-43 的异常产生是促进轻度闭合性脑损伤 (CHI) 小鼠模型中 AD 神经病理学以及突触和认知功能恶化的关键因素。我们观察到，一次轻微的 CHI 足以加剧 APP 转基因小鼠的 AD 神经病理学并加速突触和认知退化，但需要重复的轻微 CHI 才能诱导野生型动物的神经病理变化和突触可塑性、空间学习和记忆保留的损害。重要的是，暴露于单次或重复轻度CHI的动物中的这些变化可通过TDP-43的沉默而减轻，但通过TDP-43敲低的挽救而恢复。此外，海马中 TDP-43 的过度表达会加剧 AD 神经病理学并引发 APP 转基因小鼠的认知障碍，类似于单一的轻微 CHI 诱导的变化。我们进一步发现，TBI 引发的神经炎症促进 NF-κB 介导的 TDP-43 转录和表达，进而刺激 tau 磷酸化和 Aβ 形成。我们的研究结果表明，TDP-43 的过量产生在加剧 AD 神经病理学以及导致 TBI 后突触和认知能力下降方面发挥着重要作用。