Cornel 鸢尾苷通过抑制 PP2A 去甲基化来减轻 Tau 过度磷酸化。
Cornel Iridoid Glycoside Attenuates Tau Hyperphosphorylation by Inhibition of PP2A Demethylation.
机构信息
Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, 45 Changchun Street, Beijing 100053, China.
Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, 45 Changchun Street, Beijing 100053, China ; Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
出版信息
Evid Based Complement Alternat Med. 2013;2013:108486. doi: 10.1155/2013/108486. Epub 2013 Dec 19.
Aim. The aim of the present study was to investigate the effect of cornel iridoid glycoside (CIG) on tau hyperphosphorylation induced by wortmannin (WT) and GF-109203X (GFX) and the underlying mechanisms. Methods. Human neuroblastoma SK-N-SH cells were preincubated with CIG (50, 100, and 200 µg/ml, resp.) for 24 h and then exposed to 10 µM WT and 10 µM GFX for 3 h after washing out CIG. Immunohistochemistry was used to observe the microtubular cytoskeleton of the cultured cells. Western blotting was used to measure the phosphorylation level of tau protein, glycogen synthase kinase 3 β (GSK-3 β ), and protein phosphatase 2A (PP2A). The activity of PP2A was detected by a biochemical assay. Results. Preincubation of CIG significantly attenuated the WT/GFX-induced tau hyperphosphorylation at the sites of Thr205, Thr212, Ser214, Thr217, Ser396, and PHF-1 and improved the damage of morphology and microtubular cytoskeleton of the cells. CIG did not prevent the decrease in p-AKT-ser473 and p-GSK-3 β -ser9 induced by WT/GFX. However, CIG significantly elevated the activity of PP2A by reducing the demethylation of PP2A catalytic subunit (PP2Ac) at Leu309 and the ratio of PME-1/LCMT in the WT/GFX-treated cells. The results suggest that CIG may be beneficial to the treatment of AD.
目的。本研究旨在探讨山茱萸环烯醚萜苷（CIG）对渥曼青霉素（WT）和 GF-109203X（GFX）诱导的 tau 过度磷酸化的影响及其作用机制。方法。人神经母细胞瘤 SK-N-SH 细胞先用 CIG（50、100 和 200μg/ml，分别）孵育 24 h，然后用不含 CIG 的培养基洗涤后，再暴露于 10 μM WT 和 10 μM GFX 3 h。用免疫组织化学法观察培养细胞的微管细胞骨架。用 Western blot 法检测 tau 蛋白、糖原合成酶激酶 3β（GSK-3β）和蛋白磷酸酶 2A（PP2A）的磷酸化水平。用生化测定法检测 PP2A 的活性。结果。CIG 预孵育可显著减轻 WT/GFX 诱导的 tau 在 Thr205、Thr212、Ser214、Thr217、Ser396 和 PHF-1 位点的过度磷酸化，并改善细胞形态和微管细胞骨架的损伤。CIG 不能阻止 WT/GFX 诱导的 p-AKT-ser473 和 p-GSK-3β-ser9 的减少。然而，CIG 通过降低 WT/GFX 处理细胞中 PP2A 催化亚基（PP2Ac）的 Leu309 去甲基化和 PME-1/LCMT 的比值，显著提高了 PP2A 的活性。结果表明，CIG 可能有益于 AD 的治疗。
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