Cilostazol suppresses ß-amyloid production by activating a disintegrin and metalloproteinase 10 via the upregulation of SIRT1-coupled retinoic acid receptor-ß.
J Neurosci Res
; 92(11): 1581-90, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-24903973
ABSTRACT
The accumulation of plaques of ß-amyloid (Aß) peptides, a hallmark of Alzheimer's disease, results from the sequential cleavage of amyloid precursor protein (APP) by activation of ß- and γ-secretases. However, the production of Aß can be avoided by alternate cleavage of APP by α-and γ-secretases. We hypothesized that cilostazol attenuates Aß production by increasing a disintegrin and metalloproteinase 10 (ADAM10)/α-secretase activity via SIRT1-coupled retinoic acid receptor-ß (RARß) activation in N2a cells expressing human APP Swedish mutation (N2aSwe). To evoke endogenous Aß overproduction, the culture medium was switched from medium containing 10% fetal bovine serum (FBS) to medium containing 1% FBS, and cells were cultured for 3â¼24 hr. After depletion of FBS in media, N2aSwe cells showed increased accumulations of full-length APP (FL-APP) and Aß in a time-dependent manner (3-24 hr) in association with decreased ADAM10 protein expression. When pretreated with cilostazol (10-30 µM), FL-APP and Aß levels were significantly reduced, and ADAM10 and α-secretase activities were restored. Furthermore, the effect of cilostazol on ADAM10 expression was antagonized by pretreating Rp-cAMPS and sirtinol and by SIRT1-gene silencing. In the N2aSwe cells overexpressing the SIRT1 gene, ADAM10, and sAPPα levels were significantly elevated. In addition, like all-trans retinoic acid, cilostazol enhanced the protein expressions of RARß and ADAM10, and the cilostazol-stimulated ADAM10 elevation was significantly attenuated by LE135 (a RARß inhibitor), sirtinol, and RARß-gene silencing. In conclusion, cilostazol suppresses the accumulations of FL-APP and Aß by activating ADAM10 via the upregulation of SIRT1-coupled RARß.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Tetrazóis
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Regulação para Cima
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Peptídeos beta-Amiloides
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Receptores do Ácido Retinoico
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Fármacos Neuroprotetores
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Metaloproteinase 10 da Matriz
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Sirtuína 1
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Neurosci Res
Ano de publicação:
2014
Tipo de documento:
Article