GSK-3/CREB pathway involved in the gx-50's effect on Alzheimer's disease

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• 作者：Maoping Tang ; Shi Shi ; Yubing Guo ; Wangjie Xu ; Lianyun Wang ; Yi Chen ; Zhaoxia Wang ; Zhongdong Qiao ; ^{zdqiao@sjtu.edu.cn" class="auth_mail}
• 关键词：Alzheimer's disease ; Microarray analysis ; gx-50 ; Glycogen synthase kinase-3 ; cAMP response element binding protein
• 刊名：Neuropharmacology
• 出版年：June, 2014
• 年：2014
• 卷：81
• 期：Complete
• 页码：256-266
• 全文大小：4373 K

文摘

Aggregation of amyloid-beta (A尾) fragments is one of the major pathological hallmarks of Alzheimer's disease (AD). Our previous study has demonstrated that a novel compound named N-[2-(3, 4-dimethoxyphenyl) ethyl]-3-phenyl-acrylamide (gx-50) can decrease the accumulation of A尾 oligomers in the cerebral cortex and improve the cognitive abilities in transgenic demented mice. To further study the mechanism of the neuroprotective effect of gx-50 against AD, we employed microarray to investigate the gene expression profile of the primary cultured neurons treated with gx-50 or/and A尾. Microarray disclosed 351 genes associated with AD in the gx-50 plus A尾 treated group, out of the 22,523 probes. 217 of the 351 genes were significantly up-regulated, 134 of them were down-regulated. The 351 genes were mainly involved in neurotransmission, signal transduction, nervous system development, protein phosphorylation, transcription and apoptosis. By the Onto-pathway analysis, a network involved two molecules - GSK-3, CREB and another two closely linked proteins - AKT, BDNF was discovered. The GSK/CREB pathway was further studied at the gene and protein level both in聽vivo and in聽vitro. Western blot and immunohistochemistry analysis showed that the gx-50 elevated the AKT phosphorylation and inhibited its downstream protein - GSK-3鈥檚 activity, then restored the CREB's transcriptional activity, and finally enhanced the expression of the CREB target gene - BDNF. In addition, the real-time PCR results displayed the same tendency. In conclusion, studies in this research indicated that the gx-50 may improve the cognitive ability of AD via the GSK-3/CREB pathway.