PKM2 Activator TEPP-46 Suppresses Inflammation, Apoptosis, and Oxidative Disordering of Amyloid-Beta Treated Human Neuroblastoma

IF 0.5 4区医学 Q4 NEUROSCIENCES Neurochemical Journal Pub Date : 2024-05-24 DOI:10.1134/s1819712424010240

Lingling Wang, Tao Wang, Xiaohui Zhao, Haibing Ren, Jingshi Li, Juan Yang

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Abstract

Beta-amyloid peptides (Aβ) are common risk factors associated with cognitive impairment, neuroinflammation, and apoptosis in Alzheimer’s disease (AD). The glycolytic enzyme PKM2 is an essential antioxidant intermediate by promoting glutathione (GSH) biosynthesis, shielding neurons against oxidative damage, and conferring neuroprotective effects. However, its role in AD has rarely been reported. This study aimed to explore the mechanism underlying PKM2 activation in an AD cell model via the PKM2 activator TEPP-46. Aβ administration in SH-SY5Y cells reduced cell viability while increasing inflammation, apoptosis, and oxidative disorder. PKM2 activity, rather than its expression, was reduced in the AD cell model. TEPP-46 administration could restore PKM2 activity, reverse the suppressive effect of Aβ on cell viability and proliferation, reduce the expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), decrease Aβ-triggered cell apoptosis, and restore cellular oxidative stress. Furthermore, the effect of TEPP-46 on the AD cell model was confirmed by deactivating P62, reversing the Bax/Bcl-2 ratio, and activating the Nrf2/HO-1 pathway by western blotting. Additionally, colivelin, an Nrf2 antagonist, deactivates the Nrf2/HO-1 pathway and recovers oxidative stress. Colivelin administration could also offset the influence of TEPP-46 on Aβ-induced SH-SY5Y cell inflammation and apoptosis and viability.

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PKM2 激活剂 TEPP-46 可抑制经淀粉样蛋白-β 处理的人类神经母细胞瘤的炎症、凋亡和氧化紊乱

摘要β-淀粉样肽（Aβ）是阿尔茨海默病（AD）中与认知障碍、神经炎症和细胞凋亡相关的常见风险因素。糖酵解酶 PKM2 是一种重要的抗氧化中间体，它能促进谷胱甘肽（GSH）的生物合成，保护神经元免受氧化损伤，并具有神经保护作用。然而，它在 AD 中的作用却鲜有报道。本研究旨在通过 PKM2 激活剂 TEPP-46 探索 PKM2 在 AD 细胞模型中的激活机制。在SH-SY5Y细胞中施用Aβ可降低细胞活力，同时增加炎症、细胞凋亡和氧化紊乱。在AD细胞模型中，PKM2的活性降低了，而不是其表达降低了。服用 TEPP-46 可恢复 PKM2 的活性，逆转 Aβ 对细胞活力和增殖的抑制作用，降低促炎细胞因子（IL-1β、IL-6 和 TNF-α）的表达，减少 Aβ 触发的细胞凋亡，恢复细胞氧化应激。此外，TEPP-46对AD细胞模型的作用还通过去活化P62、逆转Bax/Bcl-2比率以及通过Western印迹激活Nrf2/HO-1通路得到了证实。此外，Nrf2拮抗剂可利韦林能使Nrf2/HO-1通路失活，并恢复氧化应激。服用可利韦林还能抵消 TEPP-46 对 Aβ 诱导的 SH-SY5Y 细胞炎症、凋亡和存活率的影响。

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来源期刊

Neurochemical Journal 医学-神经科学

自引率

20.00%

发文量

审稿时长

>12 weeks

期刊介绍： Neurochemical Journal (Neirokhimiya) provides a source for the communication of the latest findings in all areas of contemporary neurochemistry and other fields of relevance (including molecular biology, biochemistry, physiology, neuroimmunology, pharmacology) in an afford to expand our understanding of the functions of the nervous system. The journal presents papers on functional neurochemistry, nervous system receptors, neurotransmitters, myelin, chromaffin granules and other components of the nervous system, as well as neurophysiological and clinical aspects, behavioral reactions, etc. Relevant topics include structure and function of the nervous system proteins, neuropeptides, nucleic acids, nucleotides, lipids, and other biologically active components. The journal is devoted to the rapid publication of regular papers containing the results of original research, reviews highlighting major developments in neurochemistry, short communications, new experimental studies that use neurochemical methodology, descriptions of new methods of value for neurochemistry, theoretical material suggesting novel principles and approaches to neurochemical problems, presentations of new hypotheses and significant findings, discussions, chronicles of congresses, meetings, and conferences with short presentations of the most sensational and timely reports, information on the activity of the Russian and International Neurochemical Societies, as well as advertisements of reagents and equipment.