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

• Published in: Neuropharmacology 2014-06, Vol.81, p.256-266
• Main Authors: Tang, Maoping, Shi, Shi, Guo, Yubing, Xu, Wangjie, Wang, Lianyun, Chen, Yi, Wang, Zhaoxia, Qiao, Zhongdong
• Format: Article
• Language: English
• Subjects: Acrylamides - pharmacology; Acrylamides - therapeutic use; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Animals; Animals, Newborn; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; cAMP response element binding protein; Cells, Cultured; CREB-Binding Protein - metabolism; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen synthase kinase-3; gx-50; Humans; Mice; Mice, Transgenic; Microarray analysis; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2014.02.008

Aggregation of amyloid-beta (Aβ) 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 Aβ 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 Aβ. Microarray disclosed 351 genes associated with AD in the gx-50 plus Aβ 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 vivo and in vitro. Western blot and immunohistochemistry analysis showed that the gx-50 elevated the AKT phosphorylation and inhibited its downstream protein – GSK-3’s 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. •We established AD model by Aβ42 administration to primary rat neurons.•gx-50 up-regulated 217 genes and down-regulated 134 genes against AD model.•gx-50 educed neuro-protective effects by GSK-3/CREB pathway.