title: Cell Signaling Mechanisms by which Geniposide Regulates Insulin- Degrading Enzyme Expression in Primary Cortical Neurons.
abstract: An increasing number of studies have demonstrated that insulin-degrading enzyme (IDE) plays an essential role in both the degradation and its activity of β-amyloid (Aβ). Therefore, the regulation of IDE expression and/or modification of IDE-dependent actions are two emerging strategies for the treatment of Alzheimer's disease (AD). We previously observed that geniposide, a novel agonist of glucagon-like peptide 1 receptor (GLP-1R), could attenuate Aβ-induced neurotoxicity by regulating the expression of IDE in primary cortical neurons. However, the signal transduction mechanisms underlying this effect were not elucidated. The present study, therefore examined and explored the cell signaling transduction and molecular mechanisms by which geniposide induces the expression of IDE in primary cortical neurons. The current study revealed that LY294002 (an inhibitor for phosphatidyl inositol 3-kinase, PI3K), PP1 (inhibitor for c-Src), GW9662 (antagonist for peroxisome proliferator-activated receptor γ, PPARγ), H89 (an inhibitor for protein kinase A, PKA) and AG1478 (an antagonist for epidermal growth factor receptor, EGFR) prohibited the up-regulation of IDE induced by geniposide in primary cortical neurons. Further, geniposide also enhanced the phosphorylation of PPARγ and accelerated the release of phosphorylated FoxO1 (forkhead box O1) from nuclear fraction to the cytosol. Moreover, geniposide directly activated the activity of IDE promoter in PC12 cells, which confirmed the presence of the GLP-1 receptor. Taken together, our findings reveal for the first time the cell signaling transduction pathway of geniposide regulating the expression of IDE in neurons.
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P.R. China. znxia@cqu.edu.cn.
authors.forename: Zhining
authors.initials: Z
authors.lastname: Xia
authors.forename: Jianhui
authors.initials: J
authors.lastname: Liu
authors.forename: Fei
authors.initials: F
authors.lastname: Yin
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016391:Genes, src / Q000187:drug effects / Q000502:physiology; D007339:Insulysin / Q000378:metabolism*; D039823:Iridoids / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D016716:PC12 Cells; D047495:PPAR gamma / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D000071161:Forkhead Box Protein O1
chemical_list: D002491:Central Nervous System Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D066246:ErbB Receptors; D051858:Forkhead Transcription Factors; D007339:Insulysin; D039823:Iridoids; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C007835:geniposide; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C483803:Egfr protein, rat