Cleaved-tau: A biomarker of neuronal damage after traumatic brain injury
Cleaved-tau: A biomarker of neuronal damage after traumatic brain injury
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DOI：
10.1089/neu.2005.22.83
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发表时间：
2005-01-01
影响因子：
4.2
通讯作者：
Zemlan, FP
中科院分区：
文献类型：
--
作者：
Gabbita, SP;Scheff, SW;Zemlan, FP
来自我们实验室的先前研究表明，人的创伤性脑损伤（TBI）导致神经元定位的细胞内微管相关蛋白（MAP）-tau的蛋白水解以产生切割的tau（C-tau）。本研究评估了C-tau作为神经元损伤的生物标志物和作为用于在大鼠TBI的受控皮质撞击模型中评估神经保护剂药物功效的生物标志物的效用。脑C-tau蛋白在大鼠中进行测定，所述大鼠经受受控的皮质撞击诱导的轻度、中度或重度水平的TBI。在撞击后72小时，与假手术相比，在TBI大鼠的皮质和海马中观察到C-tau水平的显著严重程度依赖性增加（1.5-8倍）。通过测量TBI后0.25、6、24、48、72和168小时的水平来确定C-tau大鼠脑和血清时间过程。与假手术动物相比，在同侧皮质（5-16倍）和海马（2-40倍）中观察到C-tau水平的显著时间依赖性增加。C-tau水平早在TBI后6小时就增加，在损伤后168小时观察到C-tau水平达到峰值。脑C-tau水平升高与组织学确定的TBI诱导的组织损失相关。环孢菌素A（CsA），以前被证明是在大鼠TBI神经保护，对脑C-tau水平的影响进行了检查。CsA（20 mg/kg i.p.，TBI后15分钟和24小时）显著减弱了在载体处理的动物中观察到的TBI诱导的海马C-tau水平的增加，证实了CsA的神经保护作用。CsA治疗也降低了同侧皮质C-tau水平，尽管没有达到统计学显著性。CsA的神经保护作用是利用TBI诱导的组织损失的组织学测量来证实的。此外，血清C-tau水平显着增加后6小时TBI，但不是在以后的时间点。这些结果表明，C-tau是一个可靠的，定量的生物标志物，用于评估TBI诱导的神经元损伤和神经保护药物的疗效在大鼠TBI模型中的一个潜在的生物标志物。血清数据表明，C-tau水平依赖于受损的血脑屏障以及脑TBI生物标志物的释放，这对人血清TBI生物标志物的研究具有意义。
Previous studies from our laboratory indicate that traumatic brain injury TBI) in humans results in proteolysis of neuronally-localized, intracellular microtubule associated protein (MAP)-tau to produce cleaved tau (C-tau). The present study evaluated the utility of C-tau to function as a biomarker of neuronal injury and as a biomarker for evaluating neuroprotectant drug efficacy in a controlled cortical impact model of rat TBI. Brain C-tau was determined in rats subjected to controlled cortical impact-induced mild, moderate or severe levels of TBI. A significant severity-dependent increase in C-tau levels was observed in the cortex and hippocampus (1.5-8-fold) of TBI rats compared to shams 72 h after impact. C-tau rat brain and serum time course was determined by measuring levels at 0.25, 6, 24, 48, 72 and 168 h after TBI. A significant time-dependent increase in C-tau levels was observed in ipsilateral cortex (5-16-fold) and hippocampus (2-40-fold) compared to sham animals. C-tau levels increased as early as 6 h after TBI with peak C-tau levels observed 168 h after injury. Elevated brain C-tau levels were associated with TBI-induced tissue loss, which was histologically determined. The effect of cyclosporin-A (CsA), previously demonstrated to be neuroprotective in rat TBI, on brain C-tau levels was examined. CsA (20 mg/kg i.p., 15 min and 24 h after TBI) significantly attenuated the TBI-induced increase in hippocampal C-tau levels observed in vehicle-treated animals confirming CsA's neuroprotectant effect. CsA treatment also lowered ipsilateral cortical C-tau levels, although it did not reach statistical significance. CsA's neuroprotectant effect was confirmed utilizing histologic measures of TBI-induced tissue loss. In addition, serum C-tau levels were significantly increased 6 h after TBI but not at later time points. These results suggest that C-tau is a reliable, quantitative biomarker for evaluating TBI-induced neuronal injury and a potential biomarker of neuroprotectant drug efficacy in the rat TBI model. Serum data suggests that C-tau levels are dependent both on a compromised blood-brain barrier as well as release of TBI biomarkers from the brain, which has implications for the study of human serum TBI biomarkers.