The misfolding and aggregation of the tau protein into neurofibrillary tangles constitutes a central feature of tauopathies. Traumatic brain injury (TBI) has emerged as a potential risk factor, triggering the onset and progression of tauopathies. Our previous research revealed distinct polymorphisms in soluble tau oligomers originating from single versus repetitive mild TBIs. However, the mechanisms orchestrating the dissemination of TBI brain-derived tau polymorphs (TBI-BDTPs) remain elusive. In this study, we explored whether TBI-BDTPs could initiate pathological tau formation, leading to distinct pathogenic trajectories. Wild-type mice were exposed to TBI-BDTPs from sham, single-blast (SB), or repeated-blast (RB) conditions, and their memory function was assessed through behavioral assays at 2- and 8-month post-injection. Our findings revealed that RB-BDTPs induced cognitive and motor deficits, concurrently fostering the emergence of toxic tau aggregates within the injected hippocampus. Strikingly, this tau pathology propagated to cortical layers, intensifying over time. Importantly, RB-BDTP-exposed animals displayed heightened glial cell activation, NLRP3 inflammasome formation, and increased TBI biomarkers, particularly triggering the aggregation of S100B, which is indicative of a neuroinflammatory response. Collectively, our results shed light on the intricate mechanisms underlying TBI-BDTP-induced tau pathology and its association with neuroinflammatory processes. This investigation enhances our understanding of tauopathies and their interplay with neurodegenerative and inflammatory pathways following traumatic brain injury.

中文翻译：

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创伤性脑损伤衍生的病理性 tau 多晶型物在野生型小鼠中诱导独特的传播模式和神经炎症反应

tau 蛋白错误折叠并聚集成神经原纤维缠结是 tau 蛋白病的核心特征。创伤性脑损伤 (TBI) 已成为一种潜在的危险因素，引发 tau 病的发生和进展。我们之前的研究揭示了源自单一与重复轻度 TBI 的可溶性 tau 寡聚体的不同多态性。然而，协调 TBI 脑源性 tau 多态性 (TBI-BDTP) 传播的机制仍然难以捉摸。在本研究中，我们探讨了 TBI-BDTP 是否可以启动病理性 tau 形成，从而导致不同的致病轨迹。野生型小鼠在假手术、单次爆炸 (SB) 或重复爆炸 (RB) 条件下暴露于 TBI-BDTP，并通过注射后 2 个月和 8 个月的行为测定评估其记忆功能。我们的研究结果表明，RB-BDTP 会引起认知和运动缺陷，同时促进注射海马内有毒 tau 蛋白聚集的出现。引人注目的是，这种 tau 蛋白病理学传播到皮质层，并随着时间的推移而加剧。重要的是，暴露于 RB-BDTP 的动物表现出神经胶质细胞活化增强、NLRP3 炎症小体形成和 TBI 生物标志物增加，特别是触发 S100B 聚集，这表明神经炎症反应。总的来说，我们的结果揭示了 TBI-BDTP 诱导的 tau 病理学的复杂机制及其与神经炎症过程的关联。这项研究增强了我们对 tau蛋白病及其与创伤性脑损伤后神经退行性和炎症途径相互作用的理解。