Subacute NO generation induced by Alzheimer's β-amyloid in the living brain:: reversal by inhibition of the inducible NO synthase
Subacute NO generation induced by Alzheimer's β-amyloid in the living brain:: reversal by inhibition of the inducible NO synthase
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DOI：
10.1096/fj.14.11.1485
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发表时间：
2000-08-01
期刊：
影响因子：
4.8
通讯作者：
Fassbender, K
中科院分区：
文献类型：
--
作者：
Ishii, K;Muelhauser, F;Fassbender, K
与淀粉样肽（A β）沉积相邻的神经胶质活化是阿尔茨海默病的特征。我们进行了补充的体外和体内实验，以研究A β刺激诱导一氧化氮（NO）的小胶质细胞生成的程度、动力学和机制。我们发现A - β原纤维剂量依赖性诱导体内NO稳定代谢物的显著释放，其程度和时间分布与平行设计的小胶质细胞培养实验惊人地相似。然而，与干扰素γ的共刺激是体外a β诱导NO生成的先决条件，而在体内则不需要，这表明活脑中存在与a β协同激活胶质细胞的因素。因此，在阿尔茨海默病中，A β原纤维的沉积可能足以诱导神经毒性小胶质细胞产物的慢性释放，这解释了与该疾病相关的进行性神经退行性变。我们观察到，全身给予选择性iNOS抑制剂可消除体内A β诱导的NO生成，这可能对阿尔茨海默病的治疗有影响。
Glial activation contiguous to deposits of amyloid peptide (A beta) is a characteristic feature in Alzheimer's disease. We performed complementary in vitro and in vivo experiments to study the extent, kinetics, and mechanisms of microglial generation of nitric oxide (NO) induced by challenge with A beta. We showed that A beta fibrils dose-dependently induced a marked release of stable metabolites of NO in vivo that was strikingly similar regarding extent and temporal profile to the one in the parallel designed microglial cell culture experiments. However, costimulation with interferon gamma, which was a prerequisite for A beta-induced NO generation in vitro, was not required in vivo, demonstrating that factors are present in the living brain that activate glial cells synergistically with A beta. Therefore, in Alzheimer's disease, deposits of A beta fibrils alone may be sufficient to induce a chronic release of neurotoxic microglial products, explaining the progressive neurodegeneration associated with this disease. Our observation that systemic administration of selective iNOS inhibitors abolishes A beta-induced NO generation in vivo may have implications for therapy of Alzheimer's disease.