The Amyloid Precursor Protein Plays Differential Roles in the UVA
Resistance and Proliferation of Human Retinal Pigment Epithelial Cells

Fatima      Sultan; Edward   T.   Parkin

Abstract

Background: Age-related macular degeneration (AMD) can be characterised by degeneration of retinal pigment epithelial (RPE) cells and the accumulation, in retinal drusen deposits, of amyloid beta-peptides proteolytically derived, by secretases, from the amyloid precursor protein (APP). Ultraviolet (UV) light exposure is a risk factor for the development of AMD.

Objectives: In the current study, we investigated whether APP and/or its proteolysis are linked to the UVA resistance or proliferation of ARPE-19 human RPE cells.

Methods: Cell viability was determined, following UVA exposure, with prior small interfering RNA-mediated APP depletion or secretase inhibitor treatments. APP levels/proteolysis were analysed by immunoblotting. Cells were also grown in the presence/absence of secretase inhibitors to assess their effects on longer-term culture growth. Finally, the effects of APP proteolytic fragments on ARPE-19 cell proliferation were monitored following co-culture with human embryonic kidney cells stably over-expressing these fragments.

Results: Endogenous APP was depleted following UVA irradiation and β-secretase, but not α- secretase, the processing of the protein was reduced. Experimental APP depletion or γ-secretase (but not α- or β-secretase) inhibition ablated the detrimental effect of UVA on cell viability. In contrast, α-secretase, and possibly γ-secretase but not β-secretase activity, appeared to promote the longerterm proliferation of ARPE-19 cells in the absence of UVA irradiation.

Conclusion: There are clear but differential links between APP expression/proteolysis and the proliferation and UVA resistance of ARPE-19 cells indicating that the protein should be investigated further in relation to the identification of possible drug targets for the treatment of AMD.

Keywords: Amyloid precursor protein, ultraviolet, resistance, proliferation, retinal, pigment, epithelial.

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Graphical Abstract

[1] 
Klein, R.; Klein, B.E.; Knudtson, M.D.; Meuer, S.M.; Swift, M.; Gangnon, R.E. Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology,  2007, 114(2), 253-262.
[http://dx.doi.org/10.1016/j.ophtha.2006.10.040] [PMID:  17270675] 
[2] 
Wong, W.L.; Su, X.; Li, X.; Cheung, C.M.G.; Klein, R.; Cheng, C-Y.; Wong, T.Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob. Health,  2014, 2(2), e106-e116.
[http://dx.doi.org/10.1016/S2214-109X(13)70145-1] [PMID:  25104651] 
[3] 
Salvi, S.M.; Akhtar, S.; Currie, Z. Ageing changes in the eye. Postgrad. Med. J.,  2006, 82(971), 581-587.
[http://dx.doi.org/10.1136/pgmj.2005.040857] [PMID:  16954455] 
[4] 
Mathenge, W. Age-related macular degeneration Community Eye Health,  2014, 27(87), 49-50.
[PMID:  25918464] 
[5] 
Parmet, S.; Lynm, C.; Glass, R.M. JAMA patient page. Age-related macular degeneration. JAMA,  2006, 295(20), 2438-2438.
[http://dx.doi.org/10.1001/jama.295.20.2438] [PMID:  16720828] 
[6] 
Hernández-Zimbrón, L.F.; Zamora-Alvarado, R.; Ochoa-De la Paz, L.; Velez-Montoya, R.; Zenteno, E.; Gulias-Cañizo, R.; Quiroz-Mercado, H.; Gonzalez-Salinas, R. Age-related macular degeneration: New paradigms for treatment and management of AMD. Oxid. Med. Cell. Longev.,  2018, 2018, 8374647-8374647.
[http://dx.doi.org/10.1155/2018/8374647] [PMID:  29484106] 
[7] 
Chalam, K.V.; Khetpal, V.; Rusovici, R.; Balaiya, S. A review: role of ultraviolet radiation in age-related macular degeneration. Eye Contact Lens,  2011, 37(4), 225-232.
[http://dx.doi.org/10.1097/ICL.0b013e31821fbd3e] [PMID:  21646979] 
[8] 
McCubrey, J.A.; Lahair, M.M.; Franklin, R.A. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid. Redox Signal.,  2006, 8(9-10), 1775-1789.
[http://dx.doi.org/10.1089/ars.2006.8.1775] [PMID:  16987031] 
[9] 
Patton, W.P.; Chakravarthy, U.; Davies, R.J.; Archer, D.B. Comet assay of UV-induced DNA damage in retinal pigment epithelial cells Invest. Ophthalmol. Vis. Sci.,  1999, 40(13), 3268-3275.
[PMID:  10586952] 
[10] 
Roduit, R.; Schorderet, D.F. MAP kinase pathways in UV-induced apoptosis of retinal pigment epithelium ARPE19 cells Apoptosis,  2008, 13(3), 343-53.
[11] 
Sheu, S.J.; Wu, S.N. Mechanism of inhibitory actions of oxidizing agents on calcium-activated potassium current in cultured pigment epithelial cells of the human retina. Invest. Ophthalmol. Vis. Sci.,  2003, 44(3), 1237-1244.
[http://dx.doi.org/10.1167/iovs.02-0330] [PMID:  12601054] 
[12] 
Tratsk, K.S.; Thanos, S. UV irradiation causes multiple cellular changes in cultured human retinal pigment epithelium cells. Albrecht Von Graefes Arch. Klin. Exp. Ophthalmol.,  2003, 241(10), 852-859.
[http://dx.doi.org/10.1007/s00417-003-0747-0] 
[13] 
Fletcher, A.E.; Bentham, G.C.; Agnew, M.; Young, I.S.; Augood, C.; Chakravarthy, U.; de Jong, P.T.; Rahu, M.; Seland, J.; Soubrane, G.; Tomazzoli, L.; Topouzis, F.; Vingerling, J.R.; Vioque, J. Sunlight exposure, antioxidants, and age-related macular degeneration. Arch. Ophthalmol.,  2008, 126(10), 1396-1403.
[http://dx.doi.org/10.1001/archopht.126.10.1396] [PMID:  18852418] 
[14] 
Vojniković, B.; Njirić, S.; Čoklo, M.; Spanjol, J. Ultraviolet sun
  radiation and incidence of age-related macular degeneration on
  Croatian Island Rab Coll. Antropol.,  2007, 31(Suppl. 1), 43-44.
[PMID:  17469748] 
[15] 
Plestina-Borjan, I.; Klinger-Lasić, M. Long-term exposure to solar
  ultraviolet radiation as a risk factor for age-related macular
  degeneration Coll. Antropol.,  2007, 31(Suppl. 1), 33-38.
[PMID:  17469746] 
[16] 
Zhou, H.; Zhang, H.; Yu, A.; Xie, J. Association between sunlight exposure and risk of age-related macular degeneration: A meta-analysis. BMC Ophthalmol.,  2018, 18(1), 331.
[http://dx.doi.org/10.1186/s12886-018-1004-y] [PMID:  30572865] 
[17] 
Glickman, R.D. Ultraviolet phototoxicity to the retina. Eye Contact Lens,  2011, 37(4), 196-205.
[http://dx.doi.org/10.1097/ICL.0b013e31821e45a9] [PMID:  21646980] 
[18] 
Nowak, M.; Gnitecki, W.; Jurowski, P. The role of retinal oxygen  metabolism in origin of age-related macular degeneration (AMD). Klin. Oczna,  2005, 107(10-12), 715-718.
[PMID:  16619828] 
[19] 
Ashok, A.; Singh, N.; Chaudhary, S.; Bellamkonda, V.; Kritikos, A.E.; Wise, A.S.; Rana, N.; McDonald, D.; Ayyagari, R. Retinal degeneration and alzheimer’s disease: An evolving link. Int. J. Mol. Sci.,  2020, 21(19), E7290.
[http://dx.doi.org/10.3390/ijms21197290] [PMID:  33023198] 
[20] 
Wang, L.; Mao, X. Role of retinal Amyloid-β in neurodegenerative diseases: Overlapping mechanisms and emerging clinical applications. Int. J. Mol. Sci.,  2021, 22(5), 2360.
[http://dx.doi.org/10.3390/ijms22052360] [PMID:  33653000] 
[21] 
Zhao, Y.; Bhattacharjee, S.; Jones, B.M.; Hill, J.M.; Clement, C.; Sambamurti, K.; Dua, P.; Lukiw, W.J. Beta-Amyloid Precursor Protein (βAPP) Processing in Alzheimer’s Disease (AD) and Age-Related Macular Degeneration (AMD). Mol. Neurobiol.,  2015, 52(1), 533-544.
[http://dx.doi.org/10.1007/s12035-014-8886-3] [PMID:  25204496] 
[22] 
Anderson, D.H.; Talaga, K.C.; Rivest, A.J.; Barron, E.; Hageman, G.S.; Johnson, L.V. Characterization of beta amyloid assemblies in drusen: The deposits associated with aging and age-related macular degeneration. Exp. Eye Res.,  2004, 78(2), 243-256.
[http://dx.doi.org/10.1016/j.exer.2003.10.011] [PMID:  14729357] 
[23] 
Luibl, V.; Isas, J.M.; Kayed, R.; Glabe, C.G.; Langen, R.; Chen, J. Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers. J. Clin. Invest.,  2006, 116(2), 378-385.
[http://dx.doi.org/10.1172/JCI25843] [PMID:  16453022] 
[24] 
Dentchev, T.; Milam, A.H.; Lee, V.M.; Trojanowski, J.Q.; Dunaief, J.L. Amyloid-beta is found in drusen from some age-related
 macular degeneration retinas, but not in drusen from normal
 retinas Mol. Vis.,  2003, 9, 184-190.
[PMID:  12764254] 
[25] 
Ratnayaka, J.A.; Serpell, L.C.; Lotery, A.J. Dementia of the eye: the role of amyloid beta in retinal degeneration. Eye (Lond.),  2015, 29(8), 1013-1026.
[http://dx.doi.org/10.1038/eye.2015.100] [PMID:  26088679] 
[26] 
Ohno-Matsui, K. Parallel findings in age-related macular degeneration and Alzheimer’s disease. Prog. Retin. Eye Res.,  2011, 30(4), 217-238.
[http://dx.doi.org/10.1016/j.preteyeres.2011.02.004] [PMID:  21440663] 
[27] 
Johnson, L.V.; Leitner, W.P.; Rivest, A.J.; Staples, M.K.; Radeke, M.J.; Anderson, D.H. The Alzheimer’s A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc. Natl. Acad. Sci. USA,  2002, 99(18), 11830-11835.
[http://dx.doi.org/10.1073/pnas.192203399] [PMID:  12189211] 
[28] 
Prasad, T.; Zhu, P.; Verma, A.; Chakrabarty, P.; Rosario, A.M.; Golde, T.E.; Li, Q. Amyloid β peptides overexpression in retinal pigment epithelial cells via AAV-mediated gene transfer mimics AMD-like pathology in mice. Sci. Rep.,  2017, 7(1), 3222.
[http://dx.doi.org/10.1038/s41598-017-03397-2] [PMID:  28607377] 
[29] 
Dawson, D.W.; Volpert, O.V.; Gillis, P.; Crawford, S.E.; Xu, H.; Benedict, W.; Bouck, N.P. Pigment epithelium-derived factor: A potent inhibitor of angiogenesis. Science,  1999, 285(5425), 245-248.
[http://dx.doi.org/10.1126/science.285.5425.245] [PMID:  10398599] 
[30] 
Yoshida, T.; Ohno-Matsui, K.; Ichinose, S.; Sato, T.; Iwata, N.; Saido, T.C.; Hisatomi, T.; Mochizuki, M.; Morita, I. The potential role of amyloid beta in the pathogenesis of age-related macular degeneration. J. Clin. Invest.,  2005, 115(10), 2793-2800.
[http://dx.doi.org/10.1172/JCI24635] [PMID:  16167083] 
[31] 
Koyama, Y.; Matsuzaki, S.; Gomi, F.; Yamada, K.; Katayama, T.; Sato, K.; Kumada, T.; Fukuda, A.; Matsuda, S.; Tano, Y.; Tohyama, M. Induction of amyloid β accumulation by ER calcium disruption and resultant upregulation of angiogenic factors in ARPE19 cells. Invest. Ophthalmol. Vis. Sci.,  2008, 49(6), 2376-2383.
[http://dx.doi.org/10.1167/iovs.07-1067] [PMID:  18515580] 
[32] 
Andrew, R.J.; Kellett, K.A.; Thinakaran, G.; Hooper, N.M. A Greek Tragedy: The growing complexity of alzheimer amyloid precursor protein proteolysis. J. Biol. Chem.,  2016, 291(37), 19235-19244.
[http://dx.doi.org/10.1074/jbc.R116.746032] [PMID:  27474742] 
[33] 
Yuksel, M.; Tacal, O. Trafficking and proteolytic processing of amyloid precursor protein and secretases in Alzheimer’s disease development: An up-to-date review. Eur. J. Pharmacol.,  2019, 856, 172415.
[http://dx.doi.org/10.1016/j.ejphar.2019.172415] [PMID:  31132354] 
[34] 
Postina, R.; Schroeder, A.; Dewachter, I.; Bohl, J.; Schmitt, U.; Kojro, E.; Prinzen, C.; Endres, K.; Hiemke, C.; Blessing, M.; Flamez, P.; Dequenne, A.; Godaux, E.; van Leuven, F.; Fahrenholz, F. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest.,  2004, 113(10), 1456-1464.
[http://dx.doi.org/10.1172/JCI20864] [PMID:  15146243] 
[35] 
Gough, M.; Parr-Sturgess, C.; Parkin, E. Zinc metalloproteinases and amyloid Beta-Peptide metabolism: The positive side of proteolysis in Alzheimer’s disease. Biochem. Res. Int.,  2011, 2011, 721463.
[http://dx.doi.org/10.1155/2011/721463] [PMID:  21152187] 
[36] 
Dar, N.J.; Glazner, G.W. Deciphering the neuroprotective and neurogenic potential of soluble amyloid precursor protein alpha (sAPPalpha). Cellular and molecular life sciences. Cell. Mol. Life Sci.,  2020, 77(12), 2315-2330.
[http://dx.doi.org/10.1007/s00018-019-03404-x] [PMID:  31960113] 
[37] 
Araki, W.; Kitaguchi, N.; Tokushima, Y.; Ishii, K.; Aratake, H.; Shimohama, S.; Nakamura, S.; Kimura, J. Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culture. Biochem. Biophys. Res. Commun.,  1991, 181(1), 265-271.
[http://dx.doi.org/10.1016/S0006-291X(05)81412-3] [PMID:  1958195] 
[38] 
Goodman, Y.; Mattson, M.P. Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. Exp. Neurol.,  1994, 128(1), 1-12.
[http://dx.doi.org/10.1006/exnr.1994.1107] [PMID:  8070512] 
[39] 
Mattson, M.P.; Cheng, B.; Culwell, A.R.; Esch, F.S.; Lieberburg, I.; Rydel, R.E. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron,  1993, 10(2), 243-254.
[http://dx.doi.org/10.1016/0896-6273(93)90315-I] [PMID:  8094963] 
[40] 
Parkin, E.T.; Watt, N.T.; Hussain, I.; Eckman, E.A.; Eckman, C.B.; Manson, J.C.; Baybutt, H.N.; Turner, A.J.; Hooper, N.M. Cellular prion protein regulates beta-secretase cleavage of the Alzheimer’s amyloid precursor protein. Proc. Natl. Acad. Sci. USA,  2007, 104(26), 11062-11067.
[http://dx.doi.org/10.1073/pnas.0609621104] [PMID:  17573534] 
[41] 
Smith, P.K.; Krohn, R.I.; Hermanson, G.T.; Mallia, A.K.; Gartner, F.H.; Provenzano, M.D.; Fujimoto, E.K.; Goeke, N.M.; Olson, B.J.; Klenk, D.C. Measurement of protein using bicinchoninic acid. Anal. Biochem.,  1985, 150(1), 76-85.
[http://dx.doi.org/10.1016/0003-2697(85)90442-7] [PMID:  3843705] 
[42] 
Hooper, N.M.; Turner, A.J. Isolation of two differentially glycosylated forms of peptidyl-dipeptidase A (angiotensin converting enzyme) from pig brain: A re-evaluation of their role in neuropeptide metabolism. Biochem. J.,  1987, 241(3), 625-633.
[http://dx.doi.org/10.1042/bj2410625] [PMID:  2439065] 
[43] 
Almenar-Queralt, A.; Falzone, T.L.; Shen, Z.; Lillo, C.; Killian, R.L.; Arreola, A.S.; Niederst, E.D.; Ng, K.S.; Kim, S.N.; Briggs, S.P.; Williams, D.S.; Goldstein, L.S. UV irradiation accelerates amyloid precursor protein (APP) processing and disrupts APP axonal transport. J. Neurosci.,  2014, 34(9), 3320-3339.
[http://dx.doi.org/10.1523/JNEUROSCI.1503-13.2014] [PMID:  24573290] 
[44] 
Martone, R.L.; Zhou, H.; Atchison, K.; Comery, T.; Xu, J.Z.; Huang, X.; Gong, X.; Jin, M.; Kreft, A.; Harrison, B.; Mayer, S.C.; Aschmies, S.; Gonzales, C.; Zaleska, M.M.; Riddell, D.R.; Wagner, E.; Lu, P.; Sun, S.C.; Sonnenberg-Reines, J.; Oganesian, A.; Adkins, K.; Leach, M.W.; Clarke, D.W.; Huryn, D.; Abou-Gharbia, M.; Magolda, R.; Bard, J.; Frick, G.; Raje, S.; Forlow, S.B.; Balliet, C.; Burczynski, M.E.; Reinhart, P.H.; Wan, H.I.; Pangalos, M.N.; Jacobsen, J.S. Begacestat (GSI-953): A novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer’s disease. J. Pharmacol. Exp. Ther.,  2009, 331(2), 598-608.
[http://dx.doi.org/10.1124/jpet.109.152975] [PMID:  19671883] 
[45] 
Corbett, N.J.; Hooper, N.M. Soluble amyloid precursor protein α: Friend or foe? Adv. Exp. Med. Biol.,  2018, 1112, 177-183.
[http://dx.doi.org/10.1007/978-981-13-3065-0_13] [PMID:  30637698] 
[46] 
Cuesta, A.; Zambrano, A.; López, E.; Pascual, A. Thyroid hormones reverse the UV-induced repression of APP in neuroblastoma cells. FEBS Lett.,  2009, 583(14), 2401-2406.
[http://dx.doi.org/10.1016/j.febslet.2009.06.040] [PMID:  19563806] 
[47] 
Cuesta, A.; Zambrano, A.; Royo, M.; Pascual, A. The tumour suppressor p53 regulates the expression of amyloid precursor protein (APP). Biochem. J.,  2009, 418(3), 643-650.
[http://dx.doi.org/10.1042/BJ20081793] [PMID:  19049493] 
[48] 
Cheng, N.; Jiao, S.; Gumaste, A.; Bai, L.; Belluscio, L. APP
 overexpression causes Aβ-independent neuronal death through
 intrinsic apoptosis pathway. eNeuro, 2016, 3(4), ENEURO.0150-
 16.2016.. 
[http://dx.doi.org/10.1523/ENEURO.0150-16.2016] [PMID: 27517085] 
[49] 
Liu, L.; Zhou, X.; Kuang, X.; Long, C.; Liu, W.; Tang, Y.; Liu, H.; He, J.; Huang, Z.; Fan, Y.; Zhang, Q.; Shen, H. The inhibition of NOTCH2 reduces UVB-induced damage in retinal pigment epithelium cells. Mol. Med. Rep.,  2017, 16(1), 730-736.
[http://dx.doi.org/10.3892/mmr.2017.6625] [PMID:  28560393] 
[50] 
Scharfenberg, F.; Armbrust, F.; Marengo, L.; Pietrzik, C.; Becker-Pauly, C. Regulation of the alternative β-secretase meprin β by ADAM-mediated shedding. Cell. Mol. Life Sci.,  2019, 76(16), 3193-3206.
[http://dx.doi.org/10.1007/s00018-019-03179-1] [PMID:  31201463] 
[51] 
Parkin, E.T.; Trew, A.; Christie, G.; Faller, A.; Mayer, R.; Turner, A.J.; Hooper, N.M. Structure-activity relationship of hydroxamate-based inhibitors on the secretases that cleave the amyloid precursor protein, angiotensin converting enzyme, CD23, and pro-tumor necrosis factor-alpha. Biochemistry,  2002, 41(15), 4972-4981.
[http://dx.doi.org/10.1021/bi015936e] [PMID:  11939793] 
[52] 
Chasseigneaux, S.; Allinquant, B. Functions of Aβ, sAPPα and sAPPβ: Similarities and differences. J. Neurochem.,  2012, 120(Suppl. 1), 99-108.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07584.x] [PMID:  22150401] 

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DOI https://dx.doi.org/10.2174/0929866529666220217124152	Print ISSN 0929-8665
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Protein & Peptide Letters

The Amyloid Precursor Protein Plays Differential Roles in the UVA Resistance and Proliferation of Human Retinal Pigment Epithelial Cells

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