APP and age-related macular degeneration: A combination of various stresses can be summarized as the integrated stress response (ISR), in which ER stress usually occurs upstream of the ISR and activated ISR.275,276 Amyloid-β protein precursor (AβPP) is a constituent of drusen, which can accelerate ER stress and ISR.277 ISR facilitates VEGF production and angio-vascularization in endothelial and RPE, in which ATF4 is the main contributor to CNV formation in AMD.274,275 Inflammation might be the mediator between VEGF and ER stress via the MAPK signaling pathway and the P300/XBP1s/Herpud1 axis.278