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

Article type: Research Article

Authors: Jung, Cha-Gyun^{a; b; *} | Uhm, Kyung-Ok^b | Horike, Hirofumi^b | Kim, Mi-Jeong^b | Misumi, Sachiyo^a | Ishida, Akimasa^a | Ueda, Yoshimoto^a | Choi, Eun-Kyoung^c | Kim, Yong-Sun^d | Michikawa, Makoto^e | Hida, Hideki^a

Affiliations: [a] Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan | [b] Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG), Morioka, Obu, Aichi, Japan | [c] Laboratory of Cellular Aging and Neurodegeneration, Ilsong Institute of Life Science, Hallym University, Anyang, Gyeonggi-do, Korea | [d] Department of Microbiology, College of Medicine, Hallym University, Chuncheon, Gangwon-do, Korea | [e] Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan

Correspondence: [*] Correspondennce to: Cha-Gyun Jung, Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Tel.: +81 52 853 8136; Fax: +81 52 842 3069; E-mail: jung@med.nagoya-cu.ac.jp.

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.

Keywords: Alzheimer's disease, amyloid-β production, auraptene, c-Jun N-terminal kinase, γ-secretase

DOI: 10.3233/JAD-141692

Journal: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1215-1228, 2015