Ii M, Sunamoto M, Ohnishi K, Ichimori Y
Molecular Pharmacology Laboratory, Takeda Chemical Industries, Ltd., Osaka, Japan.
Brain Res. 1996 May 13;720(1-2):93-100. doi: 10.1016/0006-8993(96)00156-4.
beta-Amyloid protein (A beta) is the major component of the senile plaques in Alzheimer's disease (AD), and microglial cells have been shown to be closely associated with these plaques. However, the roles of A beta and microglial cells in pathogenesis of AD remain unclear. Incubation of rat microglial cells with A beta(1-40) caused a significant increase in nitrite, a stable metabolite of nitric oxide (NO), in culture media, while there was no detectable increase in nitrite in astrocyte-rich glial cells or cortical neurons after incubation with A beta(1-40). Nitrite production by microglial cells was also induced by A beta(1-42), but not A beta(25-35). An inhibitor of NO synthase, NG-monomethyl-L-arginine (NMMA), as well as dexamethasone and actinomycin D, dose-dependently inhibited this nitrite production. Among the various cytokines investigated such as interleukin-1, interleukin-6, tumor necrosis factor-alpha and interferon-gamma (IFN-gamma), only IFN-gamma markedly enhanced A beta-dependent nitrite production. Cultured cortical neurons were injured by microglial cells stimulated with A beta in a dose-dependent manner in the presence of IFN-gamma. Neurotoxicity caused by the A beta plus IFN-gamma-stimulated microglial cells was significantly attenuated by NMMA. Thus, although further investigations into the effect of A beta on human microglial cells are needed, it is likely that A beta-induced NO production by microglial cells is one mechanism of the neuronal death in AD.
β-淀粉样蛋白（Aβ）是阿尔茨海默病（AD）中淀粉样斑块的主要成分，并且已表明小胶质细胞与这些斑块密切相关。然而，Aβ和小胶质细胞在AD发病机制中的作用仍不清楚。用Aβ（1-40）孵育大鼠小胶质细胞会导致培养基中亚硝酸盐（一氧化氮（NO）的稳定代谢产物）显著增加，而用Aβ（1-40）孵育富含星形胶质细胞的神经胶质细胞或皮质神经元后，亚硝酸盐没有可检测到的增加。小胶质细胞产生亚硝酸盐也可由Aβ（1-42）诱导，但不能由Aβ（25-35）诱导。一氧化氮合酶抑制剂N-甲基-L-精氨酸（NMMA）以及地塞米松和放线菌素D均剂量依赖性地抑制这种亚硝酸盐的产生。在研究的各种细胞因子如白细胞介素-1、白细胞介素-6、肿瘤坏死因子-α和干扰素-γ（IFN-γ）中，只有IFN-γ显著增强了Aβ依赖性亚硝酸盐的产生。在IFN-γ存在的情况下，培养的皮质神经元受到Aβ刺激的小胶质细胞以剂量依赖性方式损伤。NMMA可显著减轻由Aβ加IFN-γ刺激的小胶质细胞引起的神经毒性。因此，尽管需要进一步研究Aβ对人小胶质细胞的影响，但小胶质细胞由Aβ诱导产生NO很可能是AD中神经元死亡的一种机制。
