State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Jiangsu Key Laboratory of Brain Disease and Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, China.
Oxid Med Cell Longev. 2022 Aug 27;2022:1544244. doi: 10.1155/2022/1544244. eCollection 2022.
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder for which there is no effective therapeutic strategy. PcActx peptide from the transcriptome of zoantharian has recently been identified and verified as a novel antagonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). In the present study, we further investigated the neuroprotective potential of PcActx peptide and its underlying mechanism of action, in an N2a/APP cell model of AD. Both Western blot and RT-PCR analysis revealed that PcActx peptide markedly inhibited the production of amyloid-related proteins and the expression of BACE1, PSEN1, and PSEN2. Moreover, PcActx peptide notably attenuated the capsaicin-stimulated calcium response and prevented the phosphorylation of CaMKII and CaMKIV (calcium-mediated proteins) in N2a/APP cells. Further investigation indicated that PcActx peptide significantly suppressed ROS generation through Nrf2 activation, followed by enhanced NQO1 and HO-1 levels. In addition, PcActx peptide remarkably improved Akt phosphorylation at Ser 473 (active) and Gsk3 phosphorylation at Ser 9 (inactive), while pharmacological inhibition of the Akt/Gsk3 pathway significantly attenuated PcActx-induced Nrf2 activation and amyloid downregulation. In conclusion, PcActx peptide functions as a TRPV1 modulator of intercellular calcium homeostasis, prevents AD-like amyloid neuropathology via Akt/Gsk3-mediated Nrf2 activation, and shows promise as an alternative therapeutic agent for AD.
阿尔茨海默病（AD）是一种进行性和不可逆转的神经退行性疾病，目前尚无有效的治疗策略。最近从珊瑚转录组中鉴定并验证了 PcActx 肽是瞬时受体电位阳离子通道亚家族 V 成员 1（TRPV1）的新型拮抗剂。在本研究中，我们进一步研究了 PcActx 肽的神经保护潜力及其作用机制，该机制在 AD 的 N2a/APP 细胞模型中。Western blot 和 RT-PCR 分析均表明 PcActx 肽可显著抑制淀粉样相关蛋白的产生和 BACE1、PSEN1 和 PSEN2 的表达。此外，PcActx 肽可显著减弱辣椒素刺激的钙反应，并防止 N2a/APP 细胞中 CaMKII 和 CaMKIV（钙介导的蛋白）的磷酸化。进一步研究表明，PcActx 肽通过 Nrf2 激活显著抑制 ROS 的产生，随后增强 NQO1 和 HO-1 水平。此外，PcActx 肽可显著提高 Akt 在 Ser 473（活性）和 Gsk3 在 Ser 9（无活性）的磷酸化，而 Akt/Gsk3 通路的药理学抑制可显著减弱 PcActx 诱导的 Nrf2 激活和淀粉样下调。总之，PcActx 肽作为细胞间钙稳态的 TRPV1 调节剂，通过 Akt/Gsk3 介导的 Nrf2 激活防止 AD 样淀粉样神经病理学，并有望成为 AD 的替代治疗药物。
