创伤性脑损伤(TBI)是认知障碍和痴呆的几种进行性神经退行性疾病的最强环境风险因素之一,其特征在于过度磷酸化tau(p-Tau)的病理积累。已经质疑小鼠闭头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病变的病理特征。使用体重减轻范例对雄性C57BL/6J小鼠进行连续5天的每日一次TBI。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)在1周进行,4周,rTBI后24周,并与假手术对照进行比较。我们对闭合性颅脑损伤小鼠模型的文献进行了系统回顾,重点是参考tau蛋白评估的研究。rTBI后1周,p-Tau的积累仅限于与上纵裂相邻的call体和血管周围空间。在大脑皮层的表层观察到p-Tau的进行性积累,以及在乳头体和皮质血管周围,下,rTBI后4至24周的脑室周围位置。相关的皮质组织病理学包括微血管损伤,神经轴索稀疏,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。在我们的系统审查中,不到1%的小鼠研究(25/3756)报道了使用免疫染色的p-Tau,其中只有3人(0.08%)报告了血管周p-Tau,这被认为是慢性创伤性脑病的决定性特征。常见报道的相关病理包括神经元丢失(23%),轴突丢失(43%),小胶质细胞活化和星形胶质细胞增生(50%,each),和β淀粉样蛋白沉积(29%)。我们的新模型,在文献系统回顾的支持下,显示闭合性头部鼠类TBI后的进行性tau病理,强调小鼠模型复制相关人类组织病理学的适用性。
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.