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

摘要

Increasing evidence has shown that beta-amyloid (Abeta) induces hyperphosphorylation of tau and contributes to Abeta toxicity. Recently, tau hyperphosphorylation by glycogen synthase kinase-3beta (GSK-3beta) 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-3beta. The inhibitory control of GSK-3beta, 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 Abeta(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3beta signal pathway. We revealed that AS extract significantly attenuated Abeta(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-3beta activity by PI3K activation. The neuroprotective effects of AS extract against Abeta(1-42) -induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 muM), a PI3K inhibitor. In addition, AS extract reversed the Abeta(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 Abeta toxicity is likely mediated by the PI3K/Akt/GSK-3beta signal pathway.