title: Auraptene increases the production of amyloid-β via c-Jun N-terminal kinase-dependent activation of γ-secretase.
abstract: Amyloid-β (Aβ) peptide plays a major role in the pathogenesis of Alzheimer's disease (AD), and is generated by β- and γ-secretase-mediated proteolytic processing of amyloid-β protein precursor (AβPP). In the present study, we investigated the effect of 118 natural compounds on Aβ production in the medium of HEK293 cells stably expressing human AβPP695 (HEK293-AβPP) using Aβ42 sandwich ELISA to find natural compounds that can modulate Aβ production. We found that a coumarin derivative of citrus fruits, auraptene, increased Aβ production. Treatment of HEK293-AβPP cells and rat primary cortical neurons with auraptene significantly increased the secretion of Aβ40, Aβ42, and the Aβ42/40 ratio. However, auraptene did not change the protein levels of the AβPP processing enzymes, a disintegrin and metalloproteinases 10 (ADAM10, α-secretase), β-site AβPP cleaving enzyme-1 (BACE-1, β-secretase), and presenilin 1 (PS1, γ-secretase component). Auraptene increased the activity of γ-secretase but not that of α- and β-secretase. Furthermore, auraptene enhanced γ-secretase-mediated production of Aβ from AβPP or AβPP-C99, but not through α- and β-secretase. Auraptene also phosphorylated c-Jun N-terminal kinase (JNK), and pretreatment with the JNK inhibitor, SP600125, reduced auraptene-induced γ-secretase activity. Overall, our results suggest that auraptene-mediated activation of JNK may contribute to the production of Aβ by promoting γ-secretase activity.
authors.affiliation: Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG), Morioka, Obu, Aichi, Japan.
authors.forename: Cha-Gyun
authors.initials: CG
authors.lastname: Jung
authors.affiliation: Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG), Morioka, Obu, Aichi, Japan.
authors.forename: Kyung-Ok
authors.initials: KO
authors.lastname: Uhm
authors.affiliation: Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG), Morioka, Obu, Aichi, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Horike
authors.affiliation: Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG), Morioka, Obu, Aichi, Japan.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Misumi
authors.affiliation: Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: Akimasa
authors.initials: A
authors.lastname: Ishida
authors.affiliation: Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: Yoshimoto
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Laboratory of Cellular Aging and Neurodegeneration, Ilsong Institute of Life Science, Hallym University, Anyang, Gyeonggi-do, Korea.
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Choi
authors.affiliation: Department of Microbiology, College of Medicine, Hallym University, Chuncheon, Gangwon-do, Korea.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Michikawa
authors.affiliation: Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hida
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002491:Central Nervous System Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000873:Anthracenes; D002491:Central Nervous System Agents; D003374:Coumarins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D047428:Protein Kinase Inhibitors; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C105832:aurapten
keywords: Alzheimer's disease; amyloid-β production; auraptene; c-Jun N-terminal kinase; γ-secretase