SOURCES AND EFFECTS OF REACTIVE OXYGEN INTERMEDIATES IN THE BRAIN

1919年，德尔·里奥·霍特加是第一个认识到小胶质细胞重要性的人。它们是大脑的巨噬细胞或吞噬细胞，也会释放出活性氧物种。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。氧爆发是由己糖单磷酸分流通过膜上的NADPH氧化酶产生超氧阴离子而产生的。佛波酯(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，它含有大约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铜离子的部位。A-β既有膜结构域，也有胞外区。我们用PMA对激活的仓鼠小胶质细胞和人单核细胞来源的巨噬细胞进行了实验，发现额外的A-β(1-40)暴露只产生少量的超氧阴离子。然而，当小胶质细胞被启动或用A-β预处理后再激活PMA时，超氧阴离子的产生有更大的增加。在没有PMA的情况下，超氧化物产生减少到在A-β(1-40)存在时的值，这比没有启动和没有刺激的情况下的值要大。结论是，存在另一个负责产生超氧化物的场所。也许这个部位就是线粒体。在阿尔茨海默病中，A-β(1-40)位于斑块外围，在那里它会导致斑块中静止的小胶质细胞产生破坏性的活性氧物种，这可能会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，因为它们是由只溶于甲酸的贝塔褶片组成的。-小胶质细胞、阿尔茨海默病、斑块、超氧化物、β-淀粉样蛋白

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