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Inhibition of glycogen synthase kinase‐3β by Angelica sinensis extract decreases β‐amyloid‐induced neurotoxicity and tau phosphorylation in cultured cortical neurons
Author(s) -
Zhang Zhaoxu,
Zhao Ruiping,
Qi Jiping,
Wen Shirong,
Tang Ying,
Wang Desheng
Publication year - 2011
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22563
Subject(s) - gsk 3 , neurotoxicity , pi3k/akt/mtor pathway , protein kinase b , hyperphosphorylation , neuroprotection , glycogen synthase , ly294002 , phosphorylation , gsk3b , creb , tau protein , chemistry , kinase , signal transduction , pharmacology , biochemistry , biology , microbiology and biotechnology , alzheimer's disease , toxicity , medicine , transcription factor , disease , organic chemistry , gene
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. © 2010 Wiley‐Liss, Inc.