S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells.
S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells.
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DOI：
10.1111/j.1582-4934.2008.00159.x
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发表时间：
2008-06
影响因子：
5.3
通讯作者：
Steardo L
中科院分区：
文献类型：
--
作者：
Esposito G;Scuderi C;Lu J;Savani C;De Filippis D;Iuvone T;Steardo L Jr;Sheen V;Steardo L
先前的研究表明，星形胶质细胞衍生的S100 B蛋白的水平，如那些发生在脑细胞外空间的持续星形胶质细胞激活，可能在阿尔茨海默病（AD）的发病作用。尽管S100 B被报道促进β淀粉样前体蛋白过度表达，但S100 B和神经纤维缠结（NFT）形成之间没有明确的机制关系。这项体外研究旨在研究S100 B是否能够破坏Wnt通路并导致tau蛋白过度磷酸化。利用蛋白质印迹、电泳迁移率变动分析、超迁移和逆转录酶-聚合酶链反应技术，已经证明微摩尔浓度的S100 B通过晚期糖基化终产物受体刺激c-Jun N-末端激酶（JNK）磷酸化，随后激活培养的人神经干细胞中的核AP-1/cJun转录。此外，如Western blot、小干扰RNA和免疫荧光分析所揭示的，S100 B诱导的JNK活化增加Dickopff-1的表达，进而促进糖原合成酶激酶3β磷酸化和β-catenin降解，导致经典Wnt途径破坏和tau蛋白过度磷酸化。这些发现提出了S100 B和tau过度磷酸化之间先前未被认识的联系，表明S100 B可以促进AD和所有其他神经炎症可能起关键作用的疾病中的NFT形成。
Previous studies suggest that levels of the astrocyte-derived S100B protein, such as those occurring in brain extra-cellular spaces consequent to persistent astroglial activation, may have a pathogenetic role in Alzheimer's disease (AD). Although S100B was reported to promote β amyloid precursor protein overexpression, no clear mechanistic relationship between S100B and formation of neurofibrillary tangles (NFTs) is established. This in vitro study has been aimed at investigating whether S100B is able to disrupt Wnt pathway and lead to tau protein hyperphosphorylation. 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.
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影响因子：
11.4
作者：
Grotewold, L;Rüther, U
通讯作者：
Rüther, U
DOI：
10.1073/pnas.0511294103
发表时间：
2006-03-07
影响因子：
11.1
作者：
Jacobs, S;Lie, DC;Evans, RM
通讯作者：
Evans, RM
影响因子：
5.5
作者：
Bianchi, Roberta;Adami, Cecilia;Donato, Rosario
通讯作者：
Donato, Rosario
影响因子：
4.8
作者：
Huttunen, HJ;Fages, C;Rauvala, H
通讯作者：
Rauvala, H
影响因子：
4.2
作者：
Griffin, WST;Sheng, JG;Mrak, RE
通讯作者：
Mrak, RE