Ethanol-induced PGE2 up-regulates Aß production through PKA/CREB signaling pathway.
Biochim Biophys Acta Mol Basis Dis
; 1863(11): 2942-2953, 2017 11.
Article
em En
| MEDLINE
| ID: mdl-28668332
ABSTRACT
Ethanol abuse aggravates dementia-associated cognitive defects through the progression of Alzheimer's disease (AD) pathophysiology. Beta-site APP-cleaving enzyme 1 (BACE1) has been considered as a key regulator of AD pathogenesis by controlling amyloid beta peptide (Aß) accumulation. In addition, previous studies reported that endoplasmic reticulum (ER) stress and neuroinflammation have been proposed in ethanol-induced neurodegeneration. Thus, we investigated the role of ER stress and PGE2, a neuroinflammation mediator, in the ethanol-stimulated BACE1 expression and Aß production. Using the human-derived neuroblastoma cell line SK-N-MC, the results show that ethanol up-regulated BACE1 expression in a dose-dependent manner. Ethanol stimulated reactive oxygen species (ROS) production, which induced CHOP expression and eIF2α phosphorylation. PBA (an ER stress inhibitor) attenuated the ethanol-increased cyclooxygenase-2 (COX-2) expression and PGE2 production. By using salubrinal (an eIF2α dephosphorylation inhibitor) or EIF2A siRNA, we found that eIF2α phosphorylation mediated the ethanol-induced COX-2 expression. In addition, COX-2-induced BACE1 up-regulation was abolished by NS-398 (a selective COX-2 inhibitor). And, PF-04418948 (an EP-2 receptor inhibitor) pretreatment reduced ethanol-induced PKA activation and CREB phosphorylation as well as ethanol-stimulated Aß production. Furthermore, 14-22 amide (a PKA inhibitor) pretreatment or CREB1 siRNA transfection suppressed the ethanol-induced BACE1 expression. In conclusion, ethanol-induced eIF2α phosphorylation stimulates COX-2 expression and PGE2 production which induces the BACE1 expression and Aß production via EP-2 receptor-dependent PKA/CREB pathway.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dinoprostona
/
Transdução de Sinais
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Regulação para Cima
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Peptídeos beta-Amiloides
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Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico
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Proteínas Quinases Dependentes de AMP Cíclico
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Etanol
Limite:
Humans
Idioma:
En
Revista:
Biochim Biophys Acta Mol Basis Dis
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Egito