title: PPAR-α agonist regulates amyloid-β generation via inhibiting BACE-1 activity in human neuroblastoma SH-SY5Y cells transfected with APPswe gene.
abstract: Alzheimer's disease is a neuroinflammatory disease and is the most common cause of dementia in the elderly. Studies have shown the beneficial effects of the peroxisome proliferator-activated receptor alpha (PPAR-α) agonists on the treatment of neuroinflammatory diseases. The aim of the present study is to examine the ability of GW7647 (a PPAR-α agonist) to regulate amyloid precursor protein (APP) amyloidogenic processing in human neuroblastoma SH-SY5Y cells transfected with APPswe gene. After administration of GW7647 for 24 h, the levels of APP, soluble APPβ (sAPPβ), and presenilin 1 (PS-1) were assessed by Western blot. Cellular culture medium levels of amyloid-β 42 (Aβ42) were analyzed by ELISA, and the activity of beta-site APP cleaving enzyme 1 (BACE-1) was measured by fluorometric assay. We found that GW7647 decreased the expression of sAPPβ and the activity of BACE-1, and also reduced Aβ42 release. However, GW7647 did not modify the levels of APP and PS-1. Furthermore, LY294002, the phosphoinositide 3-kinase (PI3-K) inhibitor, reversed the effects of GW7647 on the BACE-1 activity and the levels of sAPPβ and Aβ42. Our data demonstrate that GW7647 may reduce Aβ production via inhibiting BACE-1 activity, and this may involve in PI3-K pathway.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Chongqing, 400016, China. zhanghua0303@hotmail.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Special Wards, The Affiliated Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Chongqing, 400016, China.
authors.forename: Pei-feng
authors.initials: PF
authors.lastname: Qiao
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Chongqing, 400016, China.
authors.forename: Feng-li
authors.initials: FL
authors.lastname: Zhao
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Chongqing, 400016, China. yongyanpro@hotmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002087:Butyrates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists*; D010446:Peptide Fragments / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D053764:Presenilin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002087:Butyrates; C453899:GW 7647; D047493:PPAR alpha; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D010671:Phenylurea Compounds; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; Amyloid-β; Beta-site amyloid precursor protein cleaving enzyme 1; GW7647; Peroxisome proliferator-activated receptor alpha; Phosphoinositide 3-kinase