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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression
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Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression

机译：缺氧通过上调BACE1基因表达促进阿尔茨海默氏病的发病

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摘要

The molecular mechanism underlying the pathogenesis of the majority of cases of sporadic Alzheimer's disease (AD) is unknown. A history of stroke was found to be associated with development of some AD cases, especially in the presence of vascular risk factors. Reduced cerebral perfusion is a common vascular component among AD risk factors, and hypoxia is a direct consequence of hypoperfusion. Previously we showed that expression of the beta-site beta-amyloid precursor protein (APP) cleavage enzyme 1 (BACE1) gene BACE1 is tightly controlled at both the transcriptional and translational levels and that increased BACE1 maturation contributes to the AD pathogenesis in Down's syndrome. Here we have identified a functional hypoxia-responsive element in the BACE1 gene promoter. Hypoxia up-regulated beta-secretase cleavage of APP and amyloid-beta protein (A beta) production by increasing BACE1 gene transcription and expression both in vitro and in vivo. Hypoxia treatment markedly increased A beta deposition and neuritic plaque formation and potentiated the memory deficit in Swedish mutant APP transgenic mice. Taken together, our results clearly demonstrate that hypoxia can facilitate AD pathogenesis, and they provide a molecular mechanism linking vascular factors to AD. Our study suggests that interventions to improve cerebral perfusion may benefit AD patients.
机译：大多数散发性阿尔茨海默氏病（AD）发病机理的分子机制尚不清楚。发现中风病史与某些AD病例的发展有关，特别是在存在血管危险因素的情况下。脑灌注减少是AD危险因素中常见的血管成分，而缺氧是灌注不足的直接后果。先前我们显示，β-位β-淀粉样蛋白前体蛋白（APP）裂解酶1（BACE1）基因BACE1的表达在转录和翻译水平上都受到严格控制，并且BACE1成熟度的提高有助于唐氏综合症的AD发病机理。在这里，我们已经确定了BACE1基因启动子中的功能性缺氧反应元件。缺氧通过增加BACE1基因在体外和体内的转录和表达，上调APP和β-淀粉样蛋白（A beta）的β-分泌酶裂解。低氧治疗显着增加了瑞典突变APP转基因小鼠的Aβ沉积和神经斑块形成，并增强了记忆缺陷。综上所述，我们的结果清楚地表明了低氧可以促进AD发病，并且它们提供了将血管因子与AD关联的分子机制。我们的研究表明，改善脑灌注的干预措施可能会使AD患者受益。

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