Oligomeric amyloid β induces IL-1β processing via production of ROS: implication in Alzheimer's disease.
Oligomeric amyloid β induces IL-1β processing via production of ROS: implication in Alzheimer's disease.
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DOI：
10.1038/cddis.2013.503
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发表时间：
2013-12-19
影响因子：
9
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阿尔茨海默病（Alzheimer's disease，AD）是一种以进行性神经元丢失和认知功能下降为特征的慢性神经退行性疾病。寡聚淀粉样蛋白β（oA β）通过影响突触可塑性和抑制长时程增强参与AD的发病机制。虽然有证据表明小胶质细胞（CNS中的常驻免疫细胞）在AD的发展中具有神经毒性，但oA β是否或如何诱导小胶质细胞神经毒性的机制仍不清楚。在这里，我们发现oA β促进小胶质细胞中前白细胞介素（IL）-1 β加工成成熟的IL-1 β，从而增强小胶质细胞的神经毒性。这一过程是由caspase-1和NOD样受体家族pyrin domain containing 3（NLRP 3）活性的增加通过线粒体活性氧（ROS）和部分通过NADPH氧化酶诱导的ROS诱导的。caspase-1抑制剂Z-YVAD-FMK可抑制IL-1 β的加工，减轻小胶质细胞的神经毒性。我们的研究结果表明，在AD中，小胶质细胞可以被oA β激活，通过加工IL-1 β（一种促炎细胞因子）诱导神经炎症。
Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive neuronal loss and cognitive decline. Oligomeric amyloid β (oAβ) is involved in the pathogenesis of AD by affecting synaptic plasticity and inhibiting long-term potentiation. Although several lines of evidence suggests that microglia, the resident immune cells in the central nervous system (CNS), are neurotoxic in the development of AD, the mechanism whether or how oAβ induces microglial neurotoxicity remains unknown. Here, we show that oAβ promotes the processing of pro-interleukin (IL)-1β into mature IL-1β in microglia, which then enhances microglial neurotoxicity. The processing is induced by an increase in activity of caspase-1 and NOD-like receptor family, pyrin domain containing 3 (NLRP3) via mitochondrial reactive oxygen species (ROS) and partially via NADPH oxidase-induced ROS. The caspase-1 inhibitor Z-YVAD-FMK inhibits the processing of IL-1β, and attenuates microglial neurotoxicity. Our results indicate that microglia can be activated by oAβ to induce neuroinflammation through processing of IL-1β, a pro-inflammatory cytokine, in AD.