Amyloid β oligomers induce interleukin-1β production in primary microglia in a cathepsin B- and reactive oxygen species-dependent manner
Amyloid β oligomers induce interleukin-1β production in primary microglia in a cathepsin B- and reactive oxygen species-dependent manner
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β 淀粉样蛋白寡聚体以组织蛋白酶 B 和活性氧依赖性方式诱导原代小胶质细胞中白细胞介素 1β 的产生
DOI：
10.1016/j.bbrc.2015.02.006
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
K.
中科院分区：
文献类型：
--
作者：
Taneo;J.;Adachi;T.;Yoshida;A.;Takeyasu;K.,Takahara;K. and Inaba;K.
淀粉样蛋白β(Aβ)是阿尔茨海默病的病原体，形成两种类型的聚集体：寡聚体和纤维。这些聚集体诱导炎症反应，如小胶质细胞产生白介素1β(IL-1β)，小胶质细胞是位于大脑中的巨噬细胞样细胞。在这项研究中，我们检测了两种形式的Aβ聚集体对小鼠原代小胶质细胞产生IL-1β的影响。我们在体外以Aβ(1-42)肽为原料制备了β寡聚体和原纤维。我们用电泳法和原子力显微镜分析了这些齐聚物和原纤维的特性。有趣的是，在脂多糖存在的情况下，Aβ寡聚体而不是Aβ单体或纤维可以诱导强劲的IL-1β产生。此外，Aβ寡聚体诱导内/吞噬溶酶体破裂，从而将组织蛋白酶B释放到细胞质中。β寡聚体诱导的IL-1β的产生不仅被组织蛋白酶B抑制剂CA-074-Me抑制，而且还被活性氧(ROS)抑制剂N-乙酰半胱氨酸所抑制。随机化学交联使寡聚体诱导IL-1β的能力丧失。因此，多聚化和纤化导致Aβ寡聚体失去诱导IL-1β的能力。这些结果表明，Aβ寡聚体，而不是纤维，以组织蛋白酶B和ROS依赖的方式诱导原代小胶质细胞产生IL-1β。
Amyloid β (Aβ) peptide, a causative agent of Alzheimer's disease, forms two types of aggregates: oligomers and fibrils. These aggregates induce inflammatory responses, such as interleukin-1β (IL-1β) production by microglia, which are macrophage-like cells located in the brain. In this study, we examined the effect of the two forms of Aβ aggregates on IL-1β production in mouse primary microglia. We prepared Aβ oligomer and fibril from Aβ (1–42) peptidein vitro. We analyzed the characteristics of these oligomers and fibrils by electrophoresis and atomic force microscopy. Interestingly, Aβ oligomers but not Aβ monomers or fibrils induced robust IL-1β production in the presence of lipopolysaccharide. Moreover, Aβ oligomers induced endo/phagolysosome rupture, which released cathepsin B into the cytoplasm. Aβ oligomer-induced IL-1β production was inhibited not only by the cathepsin B inhibitor CA-074-Me but also by the reactive oxygen species (ROS) inhibitor N-acetylcysteine. Random chemical crosslinking abolished the ability of the oligomers to induce IL-1β. Thus, multimerization and fibrillization causes Aβ oligomers to lose the ability to induce IL-1β. These results indicate that Aβ oligomers, but not fibrils, induce IL-1β production in primary microglia in a cathepsin B- and ROS-dependent manner.