Guglielmotto Michela, Aragno Manuela, Autelli Riccardo, Giliberto Luca, Novo Erica, Colombatto Sebastiano, Danni Oliviero, Parola Maurizio, Smith Mark A, Perry George, Tamagno Elena, Tabaton Massimo
Department of Experimental Medicine and Oncology, University of Turin, Italy.
J Neurochem. 2009 Feb;108(4):1045-56. doi: 10.1111/j.1471-4159.2008.05858.x.
While it is well established that stroke and cerebral hypoperfusion are both significant risk factors for Alzheimer's disease, the molecular link between ischemia and amyloid precursor protein processing has only been recently established. Specifically, hypoxia significantly increases beta-site APP cleaving enzyme (BACE1) gene transcription through the over-expression of hypoxia inducible factor 1alpha, resulting in increased BACE1 secretase activity and amyloid-beta production. In this study, we significantly extend these findings both in vitro, in differentiated SK-N-BE neuroblastoma cells, and in vivo, in rats subjected to cerebral ischemia, showing that hypoxia up-regulates BACE1 expression through a biphasic mechanism. The early post-hypoxic up-regulation of BACE1 depends on the production of reactive oxygen species mediated by the sudden interruption of the mitochondrial electron transport chain, while the later expression of BACE1 is caused by hypoxia inducible factor 1alpha activation. The involvement of reactive oxygen species released by mitochondria in the BACE1 up-regulation was confirmed by the complete protection exerted by complex I inhibitors such as rotenone and diphenyl-phenylen iodonium. Moreover, the oxidative stress-mediated up-regulation of BACE1 is mediated by c-jun N terminal kinase pathway as demonstrated by the protection exerted by the silencing of c-jun N-terminal kinase isoforms 1 and 2. Our study strengthens the hypothesis that oxidative stress is a basic common mechanism of amyloid-beta accumulation.
虽然中风和脑灌注不足都是阿尔茨海默病的重要危险因素，这一点已得到充分证实，但缺血与淀粉样前体蛋白加工之间的分子联系直到最近才得以确立。具体而言，缺氧通过缺氧诱导因子1α的过度表达显著增加β位点APP裂解酶（BACE1）基因转录，导致BACE1分泌酶活性增加和β淀粉样蛋白生成增多。在本研究中，我们在体外分化的SK-N-BE神经母细胞瘤细胞以及体内大脑缺血的大鼠中显著扩展了这些发现，表明缺氧通过双相机制上调BACE1表达。缺氧后早期BACE1上调依赖于线粒体电子传递链突然中断介导的活性氧生成，而BACE1的后期表达是由缺氧诱导因子1α激活引起的。线粒体释放的活性氧参与BACE1上调这一点通过鱼藤酮和二苯基碘化膦等复合体I抑制剂所发挥的完全保护作用得以证实。此外，如c-jun N末端激酶亚型1和2的沉默所发挥的保护作用所示，BACE1的氧化应激介导上调是由c-jun N末端激酶途径介导的。我们的研究强化了氧化应激是β淀粉样蛋白积累的基本共同机制这一假说。
