Increased β-secretase activity and expression in rats following transient cerebral ischemia
Increased β-secretase activity and expression in rats following transient cerebral ischemia
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DOI：
10.1016/j.brainres.2003.09.086
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发表时间：
2004-05-29
期刊：
影响因子：
2.9
通讯作者：
Simpkins, JW
中科院分区：
文献类型：
--
作者：
Wen, Y;Onyewuchi, O;Simpkins, JW
β-和γ-分泌酶对淀粉样前体蛋白（APP）的异常蛋白水解加工是阿尔茨海默病（AD）中淀粉样斑块形成的关键。鉴定出一种乙酰基蛋白酶作为参与APP加工的β-分泌酶（β-位点APP裂解酶，BACE），为潜在的AD治疗提供了药物靶标。在目前的研究中，我们证明，雌性大鼠短暂脑缺血导致β-分泌酶活性增加30%。α-分泌酶活性没有显著增加。我们检测了缺血脑提取物中BACE 1及其类似物BACE 2的蛋白水平。BACE 1蛋白水平增加67%，而BACE 2蛋白水平在这种短暂缺血后没有变化。免疫组织化学研究表明，BACE 1蛋白增加，在缺血的新皮质，与其对侧皮质相比。此外，共定位评估表明，BACE 1与凋亡标记物TUNEL染色密切相关。这些结果可以部分解释流行病学研究，即中风后痴呆的发生率较高。此外，我们的研究结果支持了这一假设，即细胞凋亡和异常APP处理相关的事件在AD脑，并表明，抑制BACE可能有治疗作用，在预防中风后恢复痴呆。(C)2004 Elsevier B.V保留所有权利。
The aberrant proteolytic processing of the atryloid precursor protein (APP) by beta- and gamma-secretases is key to amyloid plaque formation in Alzheimer's disease (AD). Identification of an aspartyl protease as the beta-secretase (beta-site APP cleaving enzyme, BACE) involved in APP processing provides a pharmaceutical target for potential AD treatment. In the present studies, we demonstrate that transient cerebral ischemia in female rats caused a 30% increase in beta-secretase activity. alpha-Secretase activity did not increase significantly. We examined protein levels of BACE1, and its analogue BACE2, in ischemic brain extracts. BACE1 protein levels increased 67%, while BACE2 protein level did not change after such a transient ischemia. Immunohistochemical studies demonstrated that BACE1 protein was increased in the ischemic neocortex, when compared with its contralateral cortex. Further, colocalization assessment indicated that BACE1 strongly associated with staining for the apoptotic marker, TUNEL. These results may partially explain epidemiological study, which demonstrate a higher incidence of dementia after stroke. Further, our results support the hypothesis that apoptosis and aberrant APP processing are correlated events in AD brain, and suggest that inhibition of BACE may have a therapeutic effect in the prevention of dementia after stroke recovery. (C) 2004 Elsevier B.V All rights reserved.