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: Cha-Gyun Jung, Kyung-Ok Uhm, Hirofumi Horike, Mi-Jeong Kim, Sachiyo Misumi, Akimasa Ishida, Yoshimoto Ueda, Eun-Kyoung Choi, Yong-Sun Kim, Makoto Michikawa, Hideki Hida
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 43 Issue 4 Pg. 1215-28 ( 2015) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 25147119 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• APP protein, human
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Anthracenes
• Central Nervous System Agents
• Coumarins
• Membrane Proteins
• PSEN1 protein, human
• Peptide Fragments
• Presenilin-1
• Protein Kinase Inhibitors
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• pyrazolanthrone
• JNK Mitogen-Activated Protein Kinases
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• Bace1 protein, rat
• ADAM Proteins
• ADAM10 Protein
• ADAM10 protein, human
• aurapten

Topics

• ADAM Proteins (metabolism)
• ADAM10 Protein
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Anthracenes (pharmacology)
• Aspartic Acid Endopeptidases (metabolism)
• Cell Survival (drug effects)
• Central Nervous System Agents (pharmacology)
• Cerebral Cortex (drug effects, metabolism)
• Coumarins (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• HEK293 Cells
• Humans
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Membrane Proteins (metabolism)
• Neurons (drug effects, metabolism)
• Peptide Fragments (metabolism)
• Phosphorylation (drug effects)
• Presenilin-1 (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Rats, Sprague-Dawley