Cornel Iridoid Glycoside Attenuates Tau Hyperphosphorylation by Inhibition of PP2A Demethylation.
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.
Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, 45 Changchun Street, Beijing 100053, China.
Cui-Cui
CC
Yang
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.
Xue-Xian
XX
Kuai
Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, 45 Changchun Street, Beijing 100053, China.
Ya-Li
YL
Li
Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, 45 Changchun Street, Beijing 100053, China.
Li
L
Zhang
Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China ; First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Laboratory of Molecular Biology, Tianjin 300193, China.
Jian-Chun
JC
Yu
Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, 45 Changchun Street, Beijing 100053, China.
Lin
L
Li
Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, 45 Changchun Street, Beijing 100053, China.
Lan
L
Zhang