Institute for Research, Development and Innovation, International Medical University, Jalan Jalil Perkasa 19, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
School of Postgraduate Studies, International Medical University, Jalan Jalil Perkasa 19, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
Neurotoxicology. 2019 Jan;70:91-98. doi: 10.1016/j.neuro.2018.11.001. Epub 2018 Nov 5.
The cognitive impairment caused by Alzheimer's disease (AD) is associated with beta-amyloid (Aβ) 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-1β, 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 p38α 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-3β and p38α 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-1β 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-3β and p38α MAPK signalling pathways, and thus protects SH-SY5Y cells against microglia-mediated neurotoxicity.
阿尔茨海默病（AD）引起的认知障碍与β-淀粉样蛋白（Aβ）和 tau 蛋白有关，并伴有炎症。最近，一种新的炎症小体信号通路被发现。炎症小体参与执行炎症反应和导致神经退行性变的细胞焦亡。因此，炎症小体信号通路可能是 AD 的潜在治疗靶点。神经干细胞（NSC）是多能细胞，能够自我更新并分化为不同的神经细胞。NSC 治疗被认为是一种有前途的治疗方法，可以保护中枢神经系统并在受损后使其恢复。然而，其涉及的机制尚不清楚。本研究旨在探讨 NE4C 神经干细胞对小胶质细胞介导的神经毒性的保护作用，并探讨介导其作用的分子机制。NE4C 降低了 caspase-1 和 IL-1β 的水平，并减弱了 LPS 刺激的 BV2 小胶质细胞中 NLRP3 炎症小体及其相关蛋白接头凋亡相关斑点样蛋白（ASC）的水平，可能通过调节 p38α MAPK 的磷酸化来实现。从 LPS 刺激的 BV2 和 NE4C 细胞共培养物中获得的条件培养基对 LPS 刺激的 BV2 和 NE4C 细胞共培养物对 SH-SY5Y 细胞具有保护作用，减轻 tau 磷酸化和淀粉样蛋白形成，并伴有 GSK-3β 和 p38α MAPK 信号通路的下调。总之，本研究表明，NSC 治疗可能是一种对抗小胶质细胞介导的神经毒性的潜在策略。NSC 调节 NLRP3 激活和 IL-1β 分泌，这在炎症反应的启动中至关重要，从而防止小胶质细胞释放神经毒性促炎因子。这最终减少 tau 过度磷酸化和淀粉样蛋白形成，可能通过调节 GSK-3β 和 p38α MAPK 信号通路，从而保护 SH-SY5Y 细胞免受小胶质细胞介导的神经毒性。
