Cornel Iridoid Glycoside Inhibits Tau Hyperphosphorylation via Regulating Cross-Talk Between GSK-3β and PP2A Signaling

Abstract

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 Cornus officinalis. 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 in vivo and in vitro 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 in vivo and in vitro. It enhanced PP2A activity, decreased tau hyperphosphorylation, and protected cell morphology in okadaic acid (OA)-induced cell model in vitro. 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.

The Reduction of Tau Hyperphosphorylation by Cornel Iridoid Glycosides Is Mediated by Their Influence on Calpain Activity

“…In this study, CIG reduced the activation of GSK-3 β and enhanced the activation of PP2A in P301S mice and MAPT-overexpressing N2a cells. These results are consistent with those of previous observational studies, in which CIG could regulate tau phosphorylation by kinase activity [ 21 ].…”

AMI, an Indazole Derivative, Improves Parkinson’s Disease by Inhibiting Tau Phosphorylation

“…The most prominent pathological feature of PD is the loss of dopaminergic neurons in the substantia nigra. Therefore, developing a new drug that inhibits dopaminergic apoptosis may significantly improve treatment effect of PD (Yang et al, 2018a;Geibl et al, 2019). This study found that AMI has a protective effect on MPP + -induced apoptosis of SH-SY5Y cells, and this effect is accompanied by decreasing phosphorylation level of tau.…”

“…Recent studies have identified GSK-3β as a potential therapeutic target in Alzheimer's disease (Shi et al, 2019). Cornel Iridoid Glycoside, a promising agent for AD therapy, inhibits tau hyperphosphorylation via regulating cross-talk between GSK-3β and PP2A signaling (Yang et al, 2018a). Osthole decreases tau protein phosphorylation via PI3K/AKT/GSK-3β signaling pathway in AD (Yao et al, 2019).…”

Selected Natural Products in Neuroprotective Strategies for Alzheimer’s Disease—A Non-Systematic Review

“…Cornel iridoid glycoside is the main compound extracted from Cornus officinalis. The findings obtained by Yang et al [107] suggest that it may be used as a promising anti-AD drug. The results presented by the authors provide novel insights into how cornel iridoid glycoside constrains tau hyperphosphorylation.…”