Traumatic brain injury (TBI) constitutes one of the strongest environmental risk factors for several progressive neurodegenerative disorders of cognitive impairment and dementia that are characterized by the pathological accumulation of hyperphosphorylated tau (p-Tau). It has been questioned whether mouse closed-head TBI models can replicate human TBI-associated tauopathy. We conducted longitudinal histopathological characterization of a mouse closed head TBI model, with a focus on pathological features reported in human TBI-associated tauopathy. Male C57BL/6 J mice were subjected to once daily TBI for 5 consecutive days using a weight drop paradigm. Histological analyses (AT8, TDP-43, pTDP-43, NeuN, GFAP, Iba-1, MBP, SMI-312, Prussian blue, IgG, βAPP, alpha-synuclein) were conducted at 1 week, 4 weeks, and 24 weeks after rTBI and compared to sham operated controls. We conducted a systematic review of the literature for mouse models of closed-head injury focusing on studies referencing tau protein assessment. At 1-week post rTBI, p-Tau accumulation was restricted to the corpus callosum and perivascular spaces adjacent to the superior longitudinal fissure. Progressive p-Tau accumulation was observed in the superficial layers of the cerebral cortex, as well as in mammillary bodies and cortical perivascular, subpial, and periventricular locations at 4 to 24 weeks after rTBI. Associated cortical histopathologies included microvascular injury, neuroaxonal rarefaction, astroglial and microglial activation, and cytoplasmatic localization of TDP-43 and pTDP-43. In our systematic review, less than 1% of mouse studies (25/3756) reported p-Tau using immunostaining, of which only 3 (0.08%) reported perivascular p-Tau, which is considered a defining feature of chronic traumatic encephalopathy. Commonly reported associated pathologies included neuronal loss (23%), axonal loss (43%), microglial activation and astrogliosis (50%, each), and beta amyloid deposition (29%). Our novel model, supported by systematic review of the literature, indicates progressive tau pathology after closed head murine TBI, highlighting the suitability of mouse models to replicate pertinent human histopathology.

中文翻译：

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小鼠闭合性头部创伤性脑损伤复制了人类疾病的组织学 tau 病理模式：新模型的表征和文献的系统回顾


创伤性脑损伤 (TBI) 是导致认知障碍和痴呆等多种进行性神经退行性疾病的最强环境危险因素之一，其特征是过度磷酸化 tau (p-Tau) 的病理性积累。人们质疑小鼠闭头 TBI 模型是否可以复制人类 TBI 相关的 tau 蛋白病。我们对小鼠闭头 TBI 模型进行了纵向组织病理学表征，重点关注人类 TBI 相关 tau 蛋白病中报道的病理特征。雄性 C57BL/6 J 小鼠使用体重下降范例，连续 5 天每天接受一次 TBI。在第 1 周、第 4 周和第 24 周进行组织学分析（AT8、TDP-43、pTDP-43、NeuN、GFAP、Iba-1、MBP、SMI-312、普鲁士蓝、IgG、βAPP、α-突触核蛋白） rTBI 后并与假手术对照进行比较。我们对闭合性头部损伤小鼠模型的文献进行了系统回顾，重点关注引用 tau 蛋白评估的研究。 rTBI 后 1 周，p-Tau 积累仅限于胼胝体和邻近上纵裂的血管周围空间。 rTBI 后 4 至 24 周，在大脑皮层浅层以及乳头体和皮层血管周围、软脑膜下和脑室周围位置观察到进行性 p-Tau 积累。相关的皮质组织病理学包括微血管损伤、神经轴突稀疏、星形胶质细胞和小胶质细胞激活以及 TDP-43 和 pTDP-43 的细胞质定位。在我们的系统综述中，不到 1% 的小鼠研究 (25/3756) 报告了使用免疫染色的 p-Tau，其中只有 3 个 (0.08%）报告了血管周围 p-Tau，这被认为是慢性创伤性脑病的一个定义特征。常见的相关病理包括神经元丢失（23%）、轴突丢失（43%）、小胶质细胞激活和星形胶质细胞增生（各 50%）以及 β 淀粉样蛋白沉积（29%）。我们的新模型得到了系统性文献综述的支持，表明小鼠闭合头部 TBI 后进行性 tau 病理学，强调了小鼠模型复制相关人类组织病理学的适用性。