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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ansari N, Khodagholi F (2013) Molecular mechanism aspect of ER stress in Alzheimer’s disease: current approaches and future strategies. Curr Drug Targets 14:114–122
Basi GS et al (2010) Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer’s disease. Alzheimers Res Ther 2:36
Beer S et al (2013) Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-offunction mechanisms associated with pancreatitis risk. Gut 62:1616–1624
Brown MK, Naidoo N (2012) The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol 3:263
Chen M et al (2011) Mitochondria-targeted peptide MTP-131 alleviates mitochondrial dysfunction and oxidative damage in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:7027–7037
Costa RO et al (2012) Amyloid beta-induced ER stress is enhanced under mitochondrial dysfunction conditions. Neurobiol Aging 33(824):e5–e16
Doh SH, KJ, Lee KM et al (2010) Retinal ganglion cell death induced by endoplasmic reticulum stress in a chronic glaucoma model. Brain Res 13: 158–66
Elbein AD (1987) Inhibitors of the biosynthesis and processing of N-linked oligosaccharide chains. Annu Rev Biochem 56:497–534
Ferreiro E et al (2012) Mitochondrial- and endoplasmic reticulum-associated oxidative stress in Alzheimer’s disease: from pathogenesis to biomarkers. Int J Cell Biol 2012:735206
Fiorelli T, Kirouac L, Padmanabhan J (2013) Altered processing of amyloid precursor protein in cells undergoing apoptosis. PLoS One 8:e57979
Gervais FG et al (1999) Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell 97:395–406
Ghosh AK, Brindisi M, Tang J (2012) Developing beta-secretase inhibitors for treatment of Alzheimer’s disease. J Neurochem 120(Suppl 1):71–83
Ghribi O (2006) The role of the endoplasmic reticulum in the accumulation of beta-amyloid peptide in Alzheimer’s disease. Curr Mol Med 6:119–133
Giorgi C et al (2009) Structural and functional link between the mitochondrial network and the endoplasmic reticulum. Int J Biochem Cell Biol 41:1817–1827
Gorlach A, Klappa P, Kietzmann T (2006) The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal 8:1391–1418
Haynes CM, Titus EA, Cooper AA (2004) Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell 15:767–776
Hoozemans JJ et al (2012) Activation of the unfolded protein response is an early event in Alzheimer’s and Parkinson’s disease. Neurodegener Dis 10:212–215
Jing G, Wang JJ, Zhang SX (2012) ER stress and apoptosis: a new mechanism for retinal cell death. Exp Diabetes Res 2012:589589
Katayama T et al (2004) Induction of neuronal death by ER stress in Alzheimer’s disease. J Chem Neuroanat 28:67–78
Krishnamoorthy RR et al (2013) A forensic path to RGC-5 cell line identification: lessons learned. Invest Ophthalmol Vis Sci 54:5712–5719
Li X, U.K., Hashimoto T (2013) Neuronal activity and secreted amyloid β lead to altered amyloid β precursor protein and presenilin 1 interactions. . Neurobiol Dis. 50: 127–34
Li J et al (2011) Hypoxia induces beta-amyloid in association with death of RGC-5 cells in culture. Biochem Biophys Res Commun 410:40–44
Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13:385–392
Liu B et al (2009) Amyloid-peptide vaccinations reduce {beta}-amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer’s transgenic mice. Am J Pathol 175:2099–2110
Lu DC et al (2003) Caspase cleavage of the amyloid precursor protein modulates amyloid beta-protein toxicity. J Neurochem 87:733–741
Malhotra JD, Kaufman RJ (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 9:2277–2293
O’Connor T et al (2008) Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 60:988–1009
Ohta K et al (2011) Endoplasmic reticulum stress enhances gamma-secretase activity. Biochem Biophys Res Commun 416:362–366
Pandol SJ, Gorelick FS, Lugea A (2011) Environmental and genetic stressors and the unfolded protein response in exocrine pancreatic function - a hypothesis. Front Physiol 2:8
Panza F et al (2011) Interacting with gamma-secretase for treating Alzheimer’s disease: from inhibition to modulation. Curr Med Chem 18:5430–5447
Paschen W, Frandsen A (2001) Endoplasmic reticulum dysfunction—a common denominator for cell injury in acute and degenerative diseases of the brain? J Neurochem 79:719–725
Pincus D et al (2010) BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response. PLoS Biol 8:e1000415
Rao RV, Ellerby HM, Bredesen DE (2004) Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 11:372–380
Richter C et al (1995) Oxidants in mitochondria: from physiology to diseases. Biochim Biophys Acta 1271:67–74
Rizzuto R et al (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280:1763–1766
Salminen A et al (2010) Endoplasmic reticulum stress in age-related macular degeneration: trigger for neovascularization. Mol Med 16:535–542
Selkoe DJ (2001a) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766
Selkoe DJ (2001b) Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis 3:75–80
Shimazawa M et al (2007) Involvement of ER stress in retinal cell death. Mol Vis 13:578–587
Soriano S et al (2001) The amyloidogenic pathway of amyloid precursor protein (APP) is independent of its cleavage by caspases. J Biol Chem 276:29045–29050
Tamagno E et al (2008) Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J Neurochem 104:683–695
Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120:545–555
Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283:29615–29619
Van Bergen NJ et al (2009) Recharacterization of the RGC-5 retinal ganglion cell line. Invest Ophthalmol Vis Sci 50:4267–4272
Vetrivel KS et al (2008) Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta. J Biol Chem 283:19489–19498
Xiong K et al (2007) Mitochondrial respiratory inhibition and oxidative stress elevate beta-secretase (BACE1) proteins and activity in vivo in the rat retina. Exp Brain Res 181:435–446
Yoshida H (2007) ER stress and diseases. FEBS J 274:630–658
Zhang SX, Sanders E, Wang JJ (2011) Endoplasmic reticulum stress and inflammation: mechanisms and implications in diabetic retinopathy. J Ocul Biol Dis Infor 4:51–61
Zheng HKE (2006) The amyloid precursor protein: beyond amyloid. Mol Neurodegener 1:5
Acknowledgments
We thank Mr. Bingshen Li for technical assistance in Western blot, RT-PCR, and cytometry assays. This study was supported by the National Natural Science Foundation of China (81270992 and 81000376) and Key Project of Natural Science Foundation of Guangdong Province (10251008901000028).
Author information
Authors and Affiliations
Corresponding author
Additional information
Bingqian Liu, Yingting Zhu, and Jiayi Zhou contributed equally to this work.
Rights and permissions
About this article
Cite this article
Liu, B., Zhu, Y., Zhou, J. et al. Endoplasmic reticulum stress promotes amyloid-beta peptides production in RGC-5 cells. Cell Stress and Chaperones 19, 827–835 (2014). https://doi.org/10.1007/s12192-014-0506-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12192-014-0506-7