1 Department of Neurosurgery, Virginia Commonwealth University , Richmond, Virginia.
2 Department of Neurosurgery, University of South Florida College of Medicine, Tampa, Florida.
J Neurotrauma. 2018 Jan 1;35(1):157-173. doi: 10.1089/neu.2017.4999. Epub 2017 Jul 21.
Traumatic brain injury (TBI) may be a significant risk factor for development of neurodegenerative disorders such as chronic traumatic encephalopathy (CTE), post-traumatic epilepsy (PTE), and Alzheimer's (AD) and Parkinson's (PD) diseases. Chronic TBI is associated with several pathological features that are also characteristic of neurodegenerative diseases, including tau pathologies, caspase-3-mediated apoptosis, neuroinflammation, and microvascular alterations. The goal of this study was to evaluate changes following TBI in cleaved-caspase-3 and caspase-3-cleaved tau truncated at Asp421, and their relationships to cellular markers potentially associated with inflammation and blood-brain (BBB) barrier damage. We studied astrocytes (glial fibrillary acidic protein [GFAP]), microglia (ionized calcium-binding adapter molecule 1 [Iba1]), BBB (endothelial barrier antigen [EBA]), and activated microglia/macrophages (cluster of differentiation 68 [CD68]). We employed immunohistochemistry at different time points from 24 h to 3 months after controlled cortical impact (CCI) injury in rats, with particular interest in white matter. The study demonstrated that CCI caused chronic upregulation of cleaved-caspase-3 in the white matter of the corpus callosum. Increases in cleaved-caspase-3 in the corpus callosum were accompanied by accumulation of caspase-3-cleaved tau, with increasing perivascular aggregation 3 months after CCI. Immunofluorescence experiments further showed cellular co-localization of cleaved-caspase-3 with GFAP and CD68 and its adjacent localization with EBA, suggesting involvement of apoptosis and neuroinflammation in mechanisms of delayed BBB and microvascular damage that could contribute to white matter changes. This study also provides the first evidence that evolving upregulation of cleaved-caspase-3 is associated with accumulation of caspase-3-cleaved tau following experimental TBI, thus providing new insights into potential common mechanisms mediated by caspase-3 and underlying chronic TBI pathologies and neurodegenerative diseases.
创伤性脑损伤（TBI）可能是神经退行性疾病（如慢性创伤性脑病[CTE]、创伤后癫痫[PTE]、阿尔茨海默病[AD]和帕金森病[PD]）发展的重要危险因素。慢性 TBI 与几种病理特征有关，这些特征也是神经退行性疾病的特征，包括 tau 病理学、半胱天冬酶-3 介导的细胞凋亡、神经炎症和微血管改变。本研究的目的是评估 TBI 后 cleaved-caspase-3 和 caspase-3 切割 tau 的变化，这些变化截断在 Asp421 处，以及它们与潜在与炎症和血脑（BBB）屏障损伤相关的细胞标志物的关系。我们研究了星形胶质细胞（胶质纤维酸性蛋白[GFAP]）、小胶质细胞（钙结合蛋白 1[Iba1]）、BBB（内皮屏障抗原[EBA]）和激活的小胶质细胞/巨噬细胞（分化群 68[CD68]）。我们在大鼠皮质撞击（CCI）损伤后 24 小时至 3 个月的不同时间点采用免疫组织化学方法进行研究，特别关注白质。该研究表明，CCI 导致胼胝体白质中 cleaved-caspase-3 的慢性上调。胼胝体中 cleaved-caspase-3 的增加伴随着 caspase-3 切割 tau 的积累，CCI 后 3 个月时血管周围聚集增加。免疫荧光实验进一步显示 cleaved-caspase-3 与 GFAP 和 CD68 的细胞共定位及其与 EBA 的相邻定位，提示细胞凋亡和神经炎症参与了延迟性 BBB 和微血管损伤的机制，这可能导致白质变化。本研究还首次提供了证据，表明实验性 TBI 后，不断上调的 cleaved-caspase-3 与 caspase-3 切割 tau 的积累有关，从而为 caspase-3 介导的潜在共同机制及其潜在的慢性 TBI 病理学和神经退行性疾病提供了新的见解。
