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

Sultan, Fatima and Parkin, Edward (2022) The Amyloid Precursor Protein Plays Differential Roles in the UVA Resistance and Proliferation of Human Retinal Pigment Epithelial Cells. Protein and Peptide Letters, 29 (4). pp. 313-327. ISSN 0929-8665

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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 -secretase, processing of the protein was reduced. Experimental APP depletion or -secretase (but not - or β-secretase) inhibition ablated the detrimental effect of UVA on cell viability. In contrast, -secretase, and possibly -secretase but not β-secretase activity, appeared to promote the longer-term proliferation of ARPE-19 cells in the absence of UVA irradiation Conclusions: 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.