Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats.
Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats.
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发表时间：
2006
期刊：
影响因子：
2.9
通讯作者：
E. Thornton;R. Vink;P. Blumbergs;C. van den Heuvel
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作者：
E. Thornton;R. Vink;P. Blumbergs;C. van den Heuvel
淀粉样前体蛋白(APP)先前被证明在创伤性脑损伤(TBI)后增加。尽管许多研究人员认为APP的增加可能会导致神经毒性Abeta的产生并对结果有害，但APP的可溶性α形式(SAPPalpha)是淀粉样前体蛋白的非淀粉样前体蛋白的非淀粉样变性裂解的产物，此前在体外已证明该蛋白具有许多神经保护和神经营养功能。然而，到目前为止，还没有研究表明sAPPalpha在体内是否具有神经保护作用。本研究考察了在体内、创伤后给予sAPPalpha对严重冲击加速性脑损伤后大鼠功能运动结局、细胞凋亡和轴突损伤的影响。在创伤后30分钟，脑室内注射sAPPalpha，与使用旋转棒任务评估的使用赋形剂的对照组相比，显著改善了运动结果。使用针对caspase-3的抗体的免疫组织化学分析显示，与赋形剂治疗的动物相比，创伤后使用sAPPalpha治疗的动物在损伤后3天显著减少了海马CA3区和皮质内的凋亡神经细胞周膜的数量。类似地，用SAPPalpha治疗的动物在所有时间点都显示出胼胝体内轴突损伤的减少，在损伤后3天和7天这种减少都是显著的。我们的结果表明，体内应用sAPPalpha改善了大鼠严重弥漫性脑损伤后的功能结局，减少了神经细胞丢失和轴突损伤。因此，促进APP向sAPPalpha的加工可能是治疗脑外伤的一种新的治疗策略。
Amyloid precursor protein (APP) has previously been shown to increase following traumatic brain injury (TBI). Whereas a number of investigators assume that increased APP may lead to the production of neurotoxic Abeta and be deleterious to outcome, the soluble alpha form of APP (sAPPalpha) is a product of the non-amyloidogenic cleavage of amyloid precursor protein that has previously been shown in vitro to have many neuroprotective and neurotrophic functions. However, no study to date has addressed whether sAPPalpha may be neuroprotective in vivo. The present study examined the effects of in vivo, posttraumatic sAPPalpha administration on functional motor outcome, cellular apoptosis, and axonal injury following severe impact-acceleration TBI in rats. Intracerebroventricular administration of sAPPalpha at 30 min posttrauma significantly improved motor outcome compared to vehicle-treated controls as assessed using the rotarod task. Immunohistochemical analysis using antibodies directed toward caspase-3 showed that posttraumatic treatment with sAPPalpha significantly reduced the number of apoptotic neuronal perikarya within the hippocampal CA3 region and within the cortex 3 days after injury compared to vehicle-treated animals. Similarly, sAPPalpha-treated animals demonstrated a reduction in axonal injury within the corpus callosum at all time points, with the reduction being significant at both 3 and 7 days postinjury. Our results demonstrate that in vivo administration of sAPPalpha improves functional outcome and reduces neuronal cell loss and axonal injury following severe diffuse TBI in rats. Promotion of APP processing toward sAPPalpha may thus be a novel therapeutic strategy in the treatment of TBI.