Title

S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells.

Journal

Journal of cellular and molecular medicine

Volume

12

Issue

None

Pages

914-27

Date

2008-06-01

Authors

Sheen V | Scuderi C | Steardo L Jr | Iuvone T | De Filippis D | Esposito G | Savani C | Lu J | Steardo L

In general, GSK-3β phosphorylation is inhibited through the canonical Wnt signalling pathway [5]. Wnt, binding to frizzled receptor, recruits dishevelled protein, which in turn antagonizes GSK-3β activity.

For example, ongoing inflammation can trigger various cell stress-response pathways, including overexpression of the secreted glycoprotein Dickopff-1 (DKK-1). DKK-1 up-regulates GSK-3β activity, promotes tau hyper-phosphorylation, NFT formation and neuronal degeneration. Thus, DKK-1 inhibits Wnt signalling in a manner similar to Aβ, and thereby fosters a self-sustaining feedback loop resulting in cellular injury

Utilizing Western blot, electrophoretic mobility shift assay, supershift and reverse transcriptase-polymerase chain reaction techniques, it has been demonstrated that micromolar S100B concentrations stimulate c-Jun N-terminal kinase (JNK) phosphorylation through the receptor for advanced glycation ending products, and subsequently activate nuclear AP-1/cJun transcription, in cultured human neural stem cells. In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3β phosphorylation and β-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. These findings propose a previously unrecognized link between S100B and tau hyperphosphorylation, suggesting S100B can contribute to NFT formation in AD and in all other conditions in which neuroinflammation may have a crucial role.

Collectively, these studies demonstrate that the soluble, astroglial-derived S100B protein interacts with RAGE leading to the JNK phosphorylation and the pJNK-dependent up-regulation of c-Jun, a component of the AP-1 complex.

In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3-beta phosphorylation and beta-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation.

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