beta-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity
beta-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity
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DOI：
10.1016/0006-8993(96)00156-4
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发表时间：
1996-05-13
期刊：
影响因子：
2.9
通讯作者：
Ichimori, Y
中科院分区：
文献类型：
--
作者：
Ii, M;Sunamoto, M;Ichimori, Y
β-淀粉样蛋白(Aβ)是阿尔茨海默病(AD)老年斑的主要成分，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发病机制中的作用尚不清楚。大鼠小胶质细胞与Aβ(1-40)孵育后，培养液中一氧化氮(NO)的稳定代谢物亚硝酸盐显著增加，而富含星形胶质细胞或皮质神经元的亚硝酸盐在与Aβ(1-40)孵育后未检测到明显增加。Aβ(1-42)也能诱导小胶质细胞产生亚硝酸盐，但Aβ(25-35)不能诱导小胶质细胞产生亚硝酸盐。一氧化氮合酶抑制剂N-G-单甲基-L-精氨酸、地塞米松和放线菌素D可剂量依赖性地抑制这种亚硝酸盐的产生。在白介素1、白介素6、肿瘤坏死因子-α和干扰素-γ等多种细胞因子中，只有干扰素-γ显著促进Aβ依赖性亚硝酸盐的产生。在干扰素-γ存在的情况下，用Aβ以剂量依赖的方式刺激小胶质细胞损伤培养的皮质神经元。NMMA可显著减轻Aβ加干扰素-γ刺激的小胶质细胞所致的神经毒性。因此，尽管需要进一步研究Aβ对人小胶质细胞的影响，但Aβ诱导的小胶质细胞产生NO可能是AD神经元死亡的机制之一。
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, N-G-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.