Ethanol-induced PGE2 up-regulates Aβ production through PKA/CREB signaling pathway
| Autor: | Young Hyun Jung, Ho Jae Han, Amr Ahmed Gabr, Jun Sung Kim, Xaykham Onphachanh, Hyun Jik Lee, Chang Woo Chae |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway medicine.medical_specialty biology Amyloid beta Chemistry CREB Cell biology Dephosphorylation Salubrinal 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Endocrinology Internal medicine mental disorders biology.protein Unfolded protein response medicine Molecular Medicine Signal transduction Molecular Biology 030217 neurology & neurosurgery PI3K/AKT/mTOR pathway |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1863:2942-2953 |
| ISSN: | 0925-4439 0441-8948 |
| DOI: | 10.1016/j.bbadis.2017.06.020 |
| Popis: | 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 (Aβ) 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 Aβ 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 Aβ 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 Aβ production via EP-2 receptor-dependent PKA/CREB pathway. |
| Databáze: | OpenAIRE |
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