title: Endoplasmic reticulum stress promotes amyloid-beta peptides production in RGC-5 cells.
abstract: Endoplasmic reticulum (ER) stress has been implicated in various neurodegenerative diseases, including Alzheimer's disease. We have previously observed amyloid production in the retina of the Tg2576 transgenic mouse model of Alzheimer's disease. In this study, we used tunicamycin-induced ER stress in RGC-5 cells, a cell line identical to the photoreceptor cell line 661W, to investigate the effect of ER stress on production of amyloid-beta (Abeta) peptides. We found that the mRNA level of amyloid-beta precursor protein (APP) remained stable, while the protein level of amyloid-beta precursor protein (APP) was decreased, the amyloid-beta precursor protein cleaving enzymes beta-site APP-cleaving enzyme 1 and presenilin 1 were upregulated, Abeta1-40 and Abeta1-42 production were increased, and reactive oxygen species production and apoptosis markers were elevated following induction of ER stress. The protein level of Abeta degradation enzymes, neprilysin, endothelin-converting enzyme 1, and endothelin-converting enzyme 2 remained unchanged during the prolonged ER stress, showing that the generation of Abeta did not result from reduction of proteolysis by these enzymes. Inclusion of group II caspase inhibitor, Z-DEVD-FMK, increased the ER stress mediated Abeta production, suggesting that they are generated by a caspase-independent mechanism. Our findings provided evidence of a role of ER stress in Abeta peptide overproduction and apoptotic pathway activation in RGC-5 cells.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China.
authors.forename: Bingqian
authors.initials: B
authors.lastname: Liu
authors.forename: Yingting
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jiayi
authors.initials: J
authors.lastname: Zhou
authors.forename: Yantao
authors.initials: Y
authors.lastname: Wei
authors.forename: Chongde
authors.initials: C
authors.lastname: Long
authors.forename: Mengfei
authors.initials: M
authors.lastname: Chen
authors.forename: Yunlan
authors.initials: Y
authors.lastname: Ling
authors.forename: Jian
authors.initials: J
authors.lastname: Ge
authors.forename: Yehong
authors.initials: Y
authors.lastname: Zhuo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; C497251:Ddit3 protein, rat; D010446:Peptide Fragments; D053764:Presenilin-1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D014415:Tunicamycin; D051742:Transcription Factor CHOP; D053829:Amyloid Precursor Protein Secretases; C505410:Casp3 protein, rat; D053148:Caspase 3; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat