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首页> 外文期刊>Journal of neuroinflammation >Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-β production in human neuron-like cells
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Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-β production in human neuron-like cells

机译：促炎性白介素18增加人神经元样细胞中与阿尔茨海默氏病相关的淀粉样β的产生

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Background Alzheimer’s disease (AD) involves increased accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles as well as neuronal loss in various regions of the neocortex. Neuroinflammation is also present, but its role in AD is not fully understood. We previously showed increased levels of pro-inflammatory cytokine interleukin-18 (IL-18) in different regions of AD brains, where it co-localized with Aβ-plaques, as well as the ability of IL-18 to increase expression of glycogen synthase kinase-3β (GSK-3β) and cyclin dependent kinase 5, involved in hyperphosphorylation of tau-protein. Elevated IL-18 has been detected in several risk conditions for AD, including obesity, type-II diabetes, and cardiovascular diseases as well as in stress. Methods We differentiated SH-SY5Y neuroblastoma cells as neuron-like and exposed them to IL-18 for various times. We examined the protein levels of amyloid-β precursor protein (APP) and its processing products, its cleaving enzymes, involved in amyloidogenic processing of APP, and markers of apoptosis. Results IL-18 increased protein levels of the β-site APP-cleaving enzyme BACE-1, the N-terminal fragment of presenilin-1 and slightly presenilin enhancer 2, both of which are members of the γ-secretase complex, as well as Fe65, which is a binding protein of the C-terminus of APP and one regulator for GSK-3β. IL-18 also increased APP expression and phosphorylation, which preceded increased BACE-1 levels. Further, IL-18 altered APP processing, increasing Aβ40 production in particular, which was inhibited by IL-18 binding protein. Increased levels of soluble APPβ were detected in culture medium after the IL-18 exposure. IL-18 also increased anti-apoptotic bcl-xL levels, which likely counteracted the minor increase of the pro-apoptotic caspase-3. Lactate dehydrogenase activity in culture medium was unaffected. Conclusions The IL-18 induction of BACE-1, APP processing, and Aβ is likely to be linked to stress-associated adaptations in neurons during the course of normal functioning and development. However, in the course of wider changes in the aging brain, and particularly in AD, the effects of heightened or prolonged levels of IL-18 may contribute to the process of AD, including via increased Aβ.
机译：背景阿尔茨海默氏病（AD）涉及淀粉样β（Aβ）斑块和神经原纤维缠结的积累增加，以及新皮层各个区域的神经元丢失。神经炎症也存在，但其在AD中的作用尚不完全清楚。我们先前显示在AD脑的不同区域中促炎性细胞因子白介素18（IL-18）的水平升高，该区域与Aβ斑块共定位，以及IL-18增加糖原合酶表达的能力激酶3β（GSK-3β）和细胞周期蛋白依赖性激酶5，参与tau蛋白的过度磷酸化。在几种AD风险条件下都检测到IL-18升高，包括肥胖，II型糖尿病，心血管疾病以及压力。方法我们将SH-SY5Y神经母细胞瘤细胞分化为神经元样，并将其暴露于IL-18多次。我们检查了淀粉样蛋白-β前体蛋白（APP）及其加工产物的蛋白水平，其裂解酶，参与APP的淀粉样蛋白加工以及细胞凋亡的标志物。结果IL-18增加了β-位点APP裂解酶BACE-1，早老素1的N端片段和早老素增强子2的蛋白质水平，这两者都是γ-分泌酶复合物的成员，以及Fe65，它是APP C端的结合蛋白，也是GSK-3β的一种调节剂。 IL-18还增加了APP的表达和磷酸化，而BACE-1的水平则更高。此外，IL-18改变了APP的加工过程，特别是增加了Aβ40的产生，而IL-18结合蛋白抑制了该过程。暴露于IL-18后，在培养基中检测到可溶性APPβ的水平增加。 IL-18还增加了抗凋亡bcl-xL的水平，这可能抵消了促凋亡caspase-3的少量增加。培养基中的乳酸脱氢酶活性不受影响。结论IL-18诱导BACE-1，APP加工和Aβ可能与正常功能和发育过程中神经元的压力相关适应有关。然而，在衰老的大脑，尤其是AD的更广泛变化过程中，IL-18水平升高或延长的影响可能通过增加Aβ来促进AD的进程。

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