Implication of phosphatidylinositol-3 kinase/Akt/glycogen synthase kinase-3β pathway in ginsenoside Rb1's attenuation of beta-amyloid-induced neurotoxicity and tau phosphorylation.

Ginseng has long been used to alleviate many ailments, particularly those associated with aging and memory deterioration. In the present study we aimed to investigate the neuroprotective effects of ginsenoside Rb1, against Aβ(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3β signal pathway. Cortical neurons were pre-treated with ginsenoside Rb1 (20, 40, 100 μM) or LiCl (1, 5, 10 mM) for 24 h, and then were co-treated with 20 μM Aβ(1-42) for 12 h. In some experiments to evaluate the mechanism of Rb1 action, a PI3K inhibitor (LY294002 10 μM) was co-administered with Rb1 for the 24-h pretreatment. We revealed that Rb1 significantly attenuated Aβ(1-42)-induced neurotoxicity and tau hyperphosphorylation at multiple AD-related sites in a dose-dependent manner. Simultaneously, it increased the levels of phospho-Ser(473)-Akt and down-regulated GSK-3β activity by PI3K activation. The neuroprotective effects of Rb1 against Aβ(1-42)-induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 μM), a PI3K inhibitor. In addition, Rb1 reversed the Aβ(1-42)-induced decrease in phosphorylation cyclic AMP response element binding (CREB) protein, which could also be blocked by the PI3K inhibitor. All these findings suggest that Rb1 may represent a potential treatment strategy for Alzheimer's disease.

Zhao R ，Zhang Z ，Song Y ，Wang D ，Qi J ，Wen S ... -  《-》

Inhibition of glycogen synthase kinase-3β by Angelica sinensis extract decreases β-amyloid-induced neurotoxicity and tau phosphorylation in cultured cortical neurons.

Increasing evidence has shown that β-amyloid (Aβ) induces hyperphosphorylation of tau and contributes to Aβ toxicity. Recently, tau hyperphosphorylation by glycogen synthase kinase-3β (GSK-3β) activation has been emphasized as one of the pathogenic mechanisms of Alzheimer's disease (AD). The phosphoinositide 3 kinase (PI3K)/Akt pathway is known as an upstream element of GSK-3β. The inhibitory control of GSK-3β, via the PI3K/Akt pathway, is an important mechanism of cell survival. In the present study, we investigated the neuroprotective effects of Angelica sinensis (AS), a traditional Chinese herbal medicine, against Aβ(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3β signal pathway. We revealed that AS extract significantly attenuated Aβ(1-42) -induced neurotoxicity and tau hyperphosphorylation at multiple AD-related sites in a dose-dependent manner. Simultaneously, it increased the levels of phospho-Ser(473) -Akt and down-regulated GSK-3β activity by PI3K activation. The neuroprotective effects of AS extract against Aβ(1-42) -induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 μM), a PI3K inhibitor. In addition, AS extract reversed the Aβ(1-42) -induced decrease in phosphorylation cyclic AMP response element binding protein (CREB), which could be blocked by the PI3K inhibitor. These results suggest that AS-mediated neuroprotection against Aβ toxicity is likely mediated by the PI3K/Akt/GSK-3β signal pathway.

Zhang Z ，Zhao R ，Qi J ，Wen S ，Tang Y ，Wang D ... -  《-》

Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation.

Xian YF ，Mao QQ ，Wu JC ，Su ZR ，Chen JN ，Lai XP ，Ip SP ，Lin ZX ... -  《-》

Ginsenoside Rd attenuates beta-amyloid-induced tau phosphorylation by altering the functional balance of glycogen synthase kinase 3beta and protein phosphatase 2A.

Neurofibrillary tangles are aggregates of hyperphosphorylated tau that are one of the pathological hallmarks of Alzheimer's disease (AD). Tau phosphorylation is regulated by a balance of kinase and phosphatase activities. Our previous study has demonstrated that ginsenoside Rd, one of the principal active ingredients of Pana notoginseng, inhibits okadaic acid-induced tau phosphorylation in vivo and in vitro, but the underlying mechanism(s) is unknown. In this study, we showed that ginsenoside Rd pretreatment inhibited tau phosphorylation at multiple sites in beta-amyloid (Aβ)-treated cultured cortical neurons, and in vivo in both a rat and transgenic mouse model. Ginsenoside Rd not only reduced Aβ-induced increased expression of glycogen synthase kinase 3beta (GSK-3β), the most important kinase involved in tau phosphorylation, but also inhibited its activity by enhancing and attenuating its phosphorylation at Ser9 and Tyr216, respectively. Moreover, ginsenoside Rd enhanced the activity of protein phosphatase 2A (PP-2A), a key phosphatase involved in tau dephosphorylation. Finally, an in vitro biochemical assay revealed that ginsenoside Rd directly affected GSK-3β and PP-2A activities. Thus, our findings provide the first evidence that ginsenoside Rd attenuates Aβ-induced pathological tau phosphorylation by altering the functional balance of GSK-3β and PP-2A.

Li L ，Liu Z ，Liu J ，Tai X ，Hu X ，Liu X ，Wu Z ，Zhang G ，Shi M ，Zhao G ... -  《-》

[Ginsenoside Rbl attenuates beta-amyloid peptide25-35 -induced tau hyperphosphorylation in cortical neurons].

Zeng YQ ，Chen XC ，Zhu YG ，Li YK ，Peng XS ，Chen LM ，Shen J ，Huang TW ... -  《-》