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 beta-amyloid (A beta) induces hyperphosphorylation of tau and contributes to A beta toxicity. Recently, tau hyperphosphorylation by glycogen synthase kinase-3 beta (GSK-3 beta) 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-3 beta. The inhibitory control of GSK-3 beta, 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 Ar beta(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3 beta signal pathway. We revealed that AS extract significantly attenuated A beta(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-3 beta activity by PI3K activation. The neuroprotective effects of AS extract against Ar beta(1-42)-induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 mu M), a PI3K inhibitor. In addition, AS extract reversed the Ap beta(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 A beta toxicity is likely mediated by the PI3K/Akt/GSK-3 beta signal pathway. (C) 2010 Wiley-Liss, Inc.