Aβ induced dysregulation of autophagy in retinal pigment epithelium contributes to the pathogenesis of dry age-related macular degeneration

Abstract

Purpose : Intracellular amyloid beta (Aβ) in retinal pigment epithelium (RPE) has been implicated in the pathogenesis of age-related macular degeneration (AMD). This study is aimed to demonstrate that autophagic dysfunction by Aβ contributes to autophagic cell death in RPE as a possible pathogenesis of dry AMD.

Methods : After Aβ₄₂ treatment in ARPE-19 cells, we evaluated cell viability and cell death mechanism by Western blot and immunocytochemistry. In addition, we performed an intravitreal injection of Aβ to induce dry AMD mouse model.

Results : Intracellular Aβ induced non-apoptotic cell death in a dose dependent manner. Dysfunction of autophagic flux by Aβ leaded to autophagic cell death. In addition, Aβ induced lysosomal depletion as well as mitochondrial depletion. Inhibition of Aβ uptake by blocking RAGE or enhancement of autophagic flux with rapamycin effectively rescued RPE from Aβ induced cell death. In vivo, intravitreal injection of Aβ induced autophagy and cell death. Rapamycin prevents Aβ induced RPE degeneration in mouse.

Conclusions : Aβ induced dysregulation of autophagy (lysosomal impairment) and autophagic cell death in retinal pigment epithelium. We suggested autophagic dysfunction by Aβ as a pathogenesis of dry AMD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.