Program

PO2-12-13

Cornel iridoid glycoside inhibits tau pathology via regulating cross-talk between GSK-3beta and PP2A signaling

[Speaker] Cuicui Yang:1
[Co-author] Li Zhang:1, Yali Li:1, Lan Zhang:1, Lin Li:1
1:Department of Pharmacology, Xuanwu Hospital of Capital Medical University, China

Neurofibrillary pathology contributes toneuronal dysfunction and correlates with the clinical progression of Alzheimer's disease (AD). Tau phosphorylation is mainly regulated by a balance of glycogen synthase kinase-3beta(GSK-3beta) and protein phosphatase 2A (PP2A) activities. Cornel iridoid glycoside(CIG) is a main component extracted from Cornus offcinalis.
The purpose of this study was to investigate the effects of CIG on GSK-3beta and PP2A, thus to explore the mechanisms of CIG to inhibit tau hyperphosphorylation.
The results in vivo and in vitro exhibited that CIG inhibited tau hyperphosphorylation and GSK-3beta over-activation. Mechanistically, CIG attenuating GSK-3beta activity was found to be dependent on PI3K/AKT signaling pathway. There is cross-talk between GSK-3beta and PP2A signaling. In the present study, PP2A catalytic C subunit (PP2Ac) siRNA abrogated the effect CIG on PI3K/AKT/GSK-3beta. Additionally and crucially, we also found that CIG inhibited the demethylation of PP2Ac at Leu309, enhanced PP2A activity, decreased tau hyperphosphorylation, and protected cell morphology in okadaic acid (OA)-induced cell model in vitro. PP2Ac siRNA abated the inhibitoryeffect of CIG on tau hyperphosphorylation and the effect of CIG on PP2A is not affected by GSK-3beta down regulation. 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-3beta activity via promoting P13K/AKT and PP2A signaling pathways. In addition, CIG increased PP2A activity via inhibiting PME-1-induced PP2Ac demethylation. These results suggest that CIG may be a promising agent for AD therapy.

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