Protective Effects of Humanin on Okadaic Acid-Induced Neurotoxicities in Cultured Cortical Neurons
Protective Effects of Humanin on Okadaic Acid-Induced Neurotoxicities in Cultured Cortical Neurons
复制标题
DOI：
10.1007/s11064-014-1410-3
复制
发表时间：
2014-11-01
影响因子：
4.4
通讯作者：
Zhang, Ce
中科院分区：
文献类型：
--
作者：
Zhao, Jinfeng;Wang, Dan;Zhang, Ce
神经元缠结是阿尔茨海默病（AD）的病理标志，其主要由过度磷酸化的tau蛋白组成，并且与AD患者的痴呆直接相关。冈田酸（Okadaic acid，OA）是一种从海洋生物中提取的毒素，能特异性抑制蛋白磷酸酶（Protein phosphatase，PPs），包括蛋白磷酸酶1（PP1）和蛋白磷酸酶2A（PP2A），导致tau蛋白过度磷酸化。Humanin（HN）是一种由24个氨基酸组成的肽，最初被报道可以保护神经元免受AD相关细胞毒性的影响。本研究旨在测试HN是否可以减轻OA诱导的神经毒性，包括神经损伤、凋亡、自噬和tau蛋白过度磷酸化。我们发现，OA给药24 h可诱导神经元损伤，包括乳酸脱氢酶释放，细胞活力和活细胞数量减少，神经元凋亡，细胞自噬和tau蛋白过度磷酸化。用HN预处理细胞对OA诱导的神经损伤、细胞凋亡、自噬和tau蛋白过度磷酸化产生显著的保护作用。我们还发现，OA处理抑制PP2A活性和HN预处理显着减弱OA的抑制作用。这项研究首次证明，HN保护皮质神经元免受OA诱导的神经毒性，包括神经元损伤，凋亡，自噬和tau蛋白过度磷酸化。HN的保护机制可能涉及PP2A活性的恢复。
Neurofibrillary tangles are pathological hallmarks of Alzheimer's disease (AD), which are mostly composed of hyperphosphorylated tau and directly correlate with dementia in AD patients. Okadaic acid (OA), a toxin extracted from marine life, can specifically inhibit protein phosphatases (PPs), including PP1 and Protein phosphatase 2A (PP2A), resulting in tau hyperphosphorylation. Humanin (HN), a peptide of 24 amino acids, was initially reported to protect neurons from AD-related cell toxicities. The present study was designed to test if HN could attenuate OA-induced neurotoxicities, including neural insults, apoptosis, autophagy, and tau hyperphosphorylation. We found that administration of OA for 24 h induced neuronal insults, including lactate dehydrogenase released, decreased of cell viability and numbers of living cells, neuronal apoptosis, cells autophagy and tau protein hyperphosphorylation. Pretreatment of cells with HN produced significant protective effects against OA-induced neural insults, apoptosis, autophagy and tau hyperphosphorylation. We also found that OA treatment inhibited PP2A activity and HN pretreatment significantly attenuated the inhibitory effects of OA. This study demonstrated for the first time that HN protected cortical neurons against OA-induced neurotoxicities, including neuronal insults, apoptosis, autophagy, and tau hyperphosphorylation. The mechanisms underlying the protections of HN may involve restoration of PP2A activity.