Auraptene increases the production of amyloid-ß via c-Jun N-terminal kinase-dependent activation of γ-secretase.
J Alzheimers Dis
; 43(4): 1215-28, 2015.
Article
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| MEDLINE
| ID: mdl-25147119
Amyloid-ß (Aß) peptide plays a major role in the pathogenesis of Alzheimer's disease (AD), and is generated by ß- and γ-secretase-mediated proteolytic processing of amyloid-ß protein precursor (AßPP). In the present study, we investigated the effect of 118 natural compounds on Aß production in the medium of HEK293 cells stably expressing human AßPP695 (HEK293-AßPP) using Aß42 sandwich ELISA to find natural compounds that can modulate Aß production. We found that a coumarin derivative of citrus fruits, auraptene, increased Aß production. Treatment of HEK293-AßPP cells and rat primary cortical neurons with auraptene significantly increased the secretion of Aß40, Aß42, and the Aß42/40 ratio. However, auraptene did not change the protein levels of the AßPP processing enzymes, a disintegrin and metalloproteinases 10 (ADAM10, α-secretase), ß-site AßPP cleaving enzyme-1 (BACE-1, ß-secretase), and presenilin 1 (PS1, γ-secretase component). Auraptene increased the activity of γ-secretase but not that of α- and ß-secretase. Furthermore, auraptene enhanced γ-secretase-mediated production of Aß from AßPP or AßPP-C99, but not through α- and ß-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 Aß by promoting γ-secretase activity.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
/
Fármacos del Sistema Nervioso Central
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Péptidos beta-Amiloides
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Cumarinas
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Proteínas Quinasas JNK Activadas por Mitógenos
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Secretasas de la Proteína Precursora del Amiloide
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Alzheimers Dis
Asunto de la revista:
GERIATRIA
/
NEUROLOGIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Japón
Pais de publicación:
Países Bajos