SOURCES AND EFFECTS OF REACTIVE OXYGEN INTERMEDIATES IN THE BRAIN

大脑中活性氧中间体的来源和作用

• 批准号: 6290617
• 负责人: DANIEL L GILBERT
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290617
• 关键词: enzyme activity; enzyme inhibitors; free radical oxygen; human tissue; immunomodulators; interferon alpha; interferon gamma; interleukin 4; macrophage; neurochemistry; nitric oxide; nitric oxide synthase; nitrites; poly IC; tissue /cell culture

Del Rio Hortega in 1919 was the first person to recognize the importance of microglia. They are the brain macrophages or phagocytes, which also release reactive oxygen species. Their function is to get rid of unwanted cellular debris and also to kill invading microorganisms. An oxygen burst is generated by the hexose monophosphatase shunt producing the superoxide anion by the NADPH oxidase at the membrane. Phorbol myristate acetate (PMA) acts directly on this mechanism. We investigated the effect of beta amyloid (A-beta) on the production of superoxide anion of activated microglia. A-beta (1-40) is derived from the amyloid precursor protein, which contains about 700 amino acids. The cysteine rich section contains a site which can reduce cupric ions to cuprous ions. A-beta has an extracellular domain as well as a membrane domain. We experimented on activated hamster microglia and human monocyte derived macrophages with PMA, and found that additional exposure to A-beta (1-40) produced only a small quantity of superoxide anion. However, when the microglia were primed or pretreated with A-beta followed by PMA activation, there was a greater increase in superoxide anion production. Without PMA, the superoxide production was reduced to the value obtained in the presence of A-beta (1-40), which was greater than either the non-primed and non- stimulated case. The conclusion is that there is another site responsible for the superoxide production. Perhaps this site is the mitochondrion. In Alzheimers disease, A-beta (1-40) is located in the plaque periphery, where it causes the resting microglia found in plaques to produce damaging reactive oxygen species, which can attack the most vulnerable part of the nervous system, the synapses. Microglia cannot destroy the plaques because they are composed of beta pleated sheets, which are only soluble in formic acid. - microglia, Alzheimer's disease, plaques, superoxide, beta-amyloid

德尔里奥霍特加在1919年是第一个认识到小胶质细胞的重要性的人。它们是脑巨噬细胞或吞噬细胞，也释放活性氧。它们的功能是清除不需要的细胞碎片，并杀死入侵的微生物。氧爆发是由膜上的NADPH氧化酶产生超氧阴离子的己糖单磷酸酶分流产生的。佛波醇肉豆蔻酸酯（PMA）直接作用于这一机制。我们研究了β淀粉样蛋白（A-β）对激活的小胶质细胞产生超氧阴离子的影响。A-β（1-40）来源于淀粉样前体蛋白，含有约700个氨基酸。富含半胱氨酸的部分含有一个可以将铜离子还原为亚铜离子的位点。A-β具有细胞外结构域以及膜结构域。我们用PMA对激活的仓鼠小胶质细胞和人单核细胞衍生的巨噬细胞进行实验，发现额外暴露于A-β（1-40）仅产生少量的超氧阴离子。然而，当小胶质细胞引发或预处理与A-β，然后PMA激活，有一个更大的增加超氧阴离子的生产。在没有PMA的情况下，超氧化物产生降低至在A-β（1-40）存在下获得的值，其大于未引发和未刺激的情况。结论是，有另一个网站负责超氧化物的生产。也许这个网站是一个新的网站。在阿尔茨海默病中，A-β（1-40）位于斑块周边，在那里它导致斑块中发现的静息小胶质细胞产生破坏性的活性氧，这可以攻击神经系统最脆弱的部分，突触。小胶质细胞不能破坏斑块，因为它们是由β折叠片组成的，只溶于甲酸。- 小胶质细胞，阿尔茨海默病，斑块，超氧化物，β-淀粉样蛋白