The NLRP3 inflammasome is involved in the neuroprotective mechanism of neural stem cells against microglia-mediated toxicity in SH-SY5Y cells via the attenuation of tau hyperphosphorylation and amyloidogenesis
The NLRP3 inflammasome is involved in the neuroprotective mechanism of neural stem cells against microglia-mediated toxicity in SH-SY5Y cells via the attenuation of tau hyperphosphorylation and amyloidogenesis
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DOI：
10.1016/j.neuro.2018.11.001
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发表时间：
2019-01-01
期刊：
影响因子：
3.4
通讯作者：
Gan, Sook Yee
中科院分区：
文献类型：
--
作者：
Chan, Elaine Wan Ling;Krishnansamy, Sangeetha;Gan, Sook Yee
阿尔茨海默病（AD）引起的认知障碍与β-淀粉样蛋白（A β）和tau蛋白有关，并伴有炎症。最近，一种新的炎症体信号通路被发现。炎性小体参与炎症反应的执行和导致神经退行性变的自燃性死亡。因此，炎症体信号通路可能是AD的潜在治疗靶点。神经干细胞（neural stem cells，NSCs）是一种具有自我更新和分化能力的多能细胞。神经干细胞治疗被认为是保护中枢神经系统和恢复其损伤的一种有前途的治疗方法。然而，所涉及的机制仍不清楚。本研究的目的是研究NE 4C神经干细胞对小胶质细胞介导的神经毒性的保护作用，并探讨其作用的分子机制。NE 4C降低了caspase-1和IL-1 β的水平，并减弱了LPS刺激的BV 2小胶质细胞中NLRP 3炎性小体及其相关蛋白衔接子（含有C-末端caspase募集结构域（ASC）的凋亡相关斑点样蛋白）的水平，这可能是通过调节p38 α MAPK的磷酸化。从LPS刺激的BV 2和NE 4C细胞的共培养物获得的条件培养基对SH-SY 5 Y细胞表现出针对小胶质细胞介导的神经毒性的保护作用;这与tau磷酸化和淀粉样蛋白生成的减弱以及伴随GSK-3 β和p38 α MAPK信号通路的下调有关。总之，本研究表明，NSC治疗可能是一种潜在的策略，对小胶质细胞介导的神经毒性。NSC调节NLRP 3活化和IL-1 β分泌，这在炎症反应的起始中是关键的，因此防止小胶质细胞释放神经毒性促炎因子。这最终可能通过调节GSK-3 β和p38 α MAPK信号通路减少tau蛋白过度磷酸化和淀粉样蛋白生成，从而保护SH-SY 5 Y细胞免受小胶质细胞介导的神经毒性。
The cognitive impairment caused by Alzheimer's disease (AD) is associated with beta-amyloid (A beta) and tau proteins, and is accompanied by inflammation. Recently, a novel inflammasome signaling pathway has been uncovered. Inflammasomes are implicated in the execution of inflammatory responses and pyroptotic death leading to neurodegeneration. Thus, the inflammasome signaling pathway could be a potential therapeutic target for AD. Neural stem cells (NSCs) are multipotent cells that can self-renew and differentiate into distinct neural cells. NSC therapy has been considered to be a promising therapeutic approach in protecting the central nervous system and restoring it following damage. However, the mechanisms involved remain unclear. The aims of this study were to investigate the protective effects of NE4C neural stem cells against microglia-mediated neurotoxicity and to explore molecular mechanisms mediating their actions. NE4C decreased the levels of caspase-1 and IL-1 beta, and attenuated the level of the NLRP3 inflammasome and its associated protein adapter, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) in LPS-stimulated BV2 microglial cells, possibly by regulating the phosphorylation of p38 alpha MAPK. The conditioned media obtained from co-culture of LPS-stimulated BV2 and NE4C cells exhibited protective effects on SH-SY5Y cells against microglia-mediated neurotoxicity; this was associated with an attenuation of tau phosphorylation and amyloidogenesis and accompanied by down-regulation of GSK-3 beta and p38 alpha MAPK signalling pathways. In conclusion, the present study suggested that NSC therapy could be a potential strategy against microglia-mediated neurotoxicity. NSCs regulate NLRP3 activation and IL-1 beta secretion, which are critical in the initiation of the inflammatory responses, hence preventing the release of neurotoxic pro-inflammatory factors by microglia. This eventually reduces tau hyperphosphylation and amyloidogenesis, possibly through the regulation of GSK-3 beta and p38 alpha MAPK signalling pathways, and thus protects SH-SY5Y cells against microglia-mediated neurotoxicity.