Auraptene Increases the Production of Amyloid-beta via c-Jun N-Terminal Kinase-Dependent Activation of gamma-Secretase

作者：Jung Cha Gyun^*; Uhm Kyung Ok; Horike Hirofumi; Kim Mi Jeong; Misumi Sachiyo; Ishida Akimasa; Ueda Yoshimoto; Choi Eun Kyoung; Kim Yong Sun; Michikawa Makoto; Hida Hideki

来源：Journal of Alzheimer's Disease, 2015, 43(4): 1215-1228.

DOI：10.3233/JAD-141692

• Alzheimer's disease
• amyloid-beta production
• auraptene
• c-Jun N-terminal kinase
• gamma-secretase

Amyloid-beta (A beta) peptide plays a major role in the pathogenesis of Alzheimer's disease (AD), and is generated by beta- and gamma-secretase-mediated proteolytic processing of amyloid-beta protein precursor (A beta PP). In the present study, we investigated the effect of 118 natural compounds on A beta production in the medium of HEK293 cells stably expressing human A beta PP695 (HEK293-A beta PP) using A beta 42 sandwich ELISA to find natural compounds that can modulate A beta production. We found that a coumarin derivative of citrus fruits, auraptene, increased A beta production. Treatment of HEK293-A beta PP cells and rat primary cortical neurons with auraptene significantly increased the secretion of A beta 40, A beta 42, and the A beta 42/40 ratio. However, auraptene did not change the protein levels of the A beta PP processing enzymes, a disintegrin and metalloproteinases 10 (ADAM10, alpha-secretase), beta-site A beta PP cleaving enzyme-1 (BACE-1, beta-secretase), and presenilin 1 (PS1, gamma-secretase component). Auraptene increased the activity of gamma-secretase but not that of alpha- and beta-secretase. Furthermore, auraptene enhanced gamma-secretase-mediated production of A beta from A beta PP or A beta PP-C99, but not through alpha- and beta-secretase. Auraptene also phosphorylated c-Jun N-terminal kinase (JNK), and pretreatment with the JNK inhibitor, SP600125, reduced auraptene-induced gamma-secretase activity. Overall, our results suggest that auraptene-mediated activation of JNK may contribute to the production of A beta by promoting gamma-secretase activity.

• 出版日期2015