Thornton Emma, Vink Robert, Blumbergs Peter C, Van Den Heuvel Corinna
Department of Pathology Level 3, Medical School North, The University of Adelaide South Australia, Australia 5005.
Brain Res. 2006 Jun 13;1094(1):38-46. doi: 10.1016/j.brainres.2006.03.107. Epub 2006 May 15.
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.
淀粉样前体蛋白（APP）先前已被证明在创伤性脑损伤（TBI）后会增加。尽管许多研究人员认为APP增加可能导致神经毒性β淀粉样蛋白（Aβ）的产生并对预后有害，但APP的可溶性α形式（sAPPα）是淀粉样前体蛋白非淀粉样生成性裂解的产物，先前已在体外显示其具有许多神经保护和神经营养功能。然而，迄今为止尚无研究探讨sAPPα在体内是否具有神经保护作用。本研究检测了创伤后体内给予sAPPα对大鼠重度撞击-加速性TBI后运动功能结局、细胞凋亡和轴突损伤的影响。与使用旋转棒试验评估的溶剂处理对照组相比，创伤后30分钟脑室内给予sAPPα显著改善了运动功能结局。使用针对半胱天冬酶-3的抗体进行的免疫组织化学分析表明，与溶剂处理的动物相比，创伤后用sAPPα治疗在损伤后3天显著减少了海马CA3区和皮质内凋亡神经元胞体的数量。同样，sAPPα处理的动物在所有时间点胼胝体内的轴突损伤均减少，在损伤后3天和7天减少均显著。我们的结果表明，体内给予sAPPα可改善大鼠重度弥漫性TBI后的功能结局，并减少神经元细胞丢失和轴突损伤。因此，促进APP加工生成sAPPα可能是治疗TBI的一种新的治疗策略。
