Yang Cuicui, Li Xuelian, Gao Wenbin, Wang Qi, Zhang Li, Li Yali, Li Lin, Zhang Lan
Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing, China.
Beijing Institute for Brain Disorders, Beijing, China.
Front Pharmacol. 2018 Jun 26;9:682. doi: 10.3389/fphar.2018.00682. eCollection 2018.
Neurofibrillary pathology contributes to neuronal dysfunction and correlates with the clinical progression of Alzheimer's disease (AD). Tau phosphorylation is mainly regulated by a balance of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) activities. Cornel iridoid glycoside (CIG) is a main component extracted from . The purpose of this study was to investigate the effects of CIG on GSK-3β and PP2A, thus to explore the mechanisms of CIG to inhibit tau hyperphosphorylation. The rat model of tau hyperphosphorylation was established by intraventricular injection of wortmannin and GF-109203X (GFX) to activate GSK-3β. The results showed that intragastrical administration of CIG inhibited tau hyperphosphorylation in the brain of rats induced by wortmannin/GFX. The results and exhibited that CIG inhibited tau hyperphosphorylation and GSK-3β over-activation. In the mechanism of action, CIG's attenuating GSK-3β activity was found to be dependent on PI3K/AKT signaling pathway. PP2A catalytic C subunit (PP2Ac) siRNA abrogated the effect of CIG on PI3K/AKT/GSK-3β. Additionally and crucially, we also found that CIG inhibited the demethylation of PP2Ac at Leu309 and . It enhanced PP2A activity, decreased tau hyperphosphorylation, and protected cell morphology in okadaic acid (OA)-induced cell model . PP2Ac siRNA abated the inhibitory effect of CIG on tau hyperphosphorylation. Moreover, CIG inhibited protein phosphatase methylesterase-1 (PME-1) and demethylation of PP2Ac, enhanced PP2A activity, and decreased tau hyperphosphorylation in PME-1-transfectd cells. Taken together, CIG inhibited GSK-3β activity via promoting P13K/AKT and PP2A signaling pathways. In addition, CIG also elevated PP2A activity via inhibiting PME-1-induced PP2Ac demethylation to inhibit GSK-3β activity, thus regulated the cross-talk between GSK-3β and PP2A signaling and consequently inhibited tau hyperphosphorylation. These results suggest that CIG may be a promising agent for AD therapy.
神经原纤维病理改变会导致神经元功能障碍，并与阿尔茨海默病（AD）的临床进展相关。tau蛋白磷酸化主要受糖原合酶激酶-3β（GSK-3β）和蛋白磷酸酶2A（PP2A）活性平衡的调节。山茱萸环烯醚萜苷（CIG）是从……中提取的主要成分。本研究的目的是探讨CIG对GSK-3β和PP2A的影响，从而探究CIG抑制tau蛋白过度磷酸化的机制。通过脑室内注射渥曼青霉素和GF-109203X（GFX）激活GSK-3β建立tau蛋白过度磷酸化大鼠模型。结果显示，胃内给予CIG可抑制渥曼青霉素/GFX诱导的大鼠脑内tau蛋白过度磷酸化。结果……表明CIG抑制tau蛋白过度磷酸化和GSK-3β过度激活。在作用机制方面，发现CIG减弱GSK-3β活性依赖于PI3K/AKT信号通路。PP2A催化C亚基（PP2Ac）的小干扰RNA（siRNA）消除了CIG对PI3K/AKT/GSK-3β的作用。此外且至关重要的是，我们还发现CIG抑制PP2Ac在亮氨酸309处的去甲基化……。在冈田酸（OA）诱导的细胞模型中，它增强PP2A活性，减少tau蛋白过度磷酸化，并保护细胞形态。PP2Ac siRNA减弱了CIG对tau蛋白过度磷酸化的抑制作用。此外，CIG在转染PME-1的细胞中抑制蛋白磷酸酶甲基酯酶-1（PME-1）和PP2Ac的去甲基化，增强PP2A活性，并减少tau蛋白过度磷酸化。综上所述，CIG通过促进PI3K/AKT和PP2A信号通路抑制GSK-3β活性。此外，CIG还通过抑制PME-1诱导的PP2Ac去甲基化来提高PP2A活性，从而抑制GSK-3β活性，进而调节GSK-3β和PP2A信号之间的相互作用，最终抑制tau蛋白过度磷酸化。这些结果表明CIG可能是一种有前景的AD治疗药物。
