Title: Soluble oligomeric Amyloid-β induced retinal pigment epithelial degeneration requires non-canonical inflammsome activation

Abstract

Purpose : Purpose:
Amyloid-β (Aβ) is a component of drusen in macular degeneration. Although several studies have established the role of Aβ in the development and progression of RPE degeneration, the mechanism of Aβ-induced cell death is still unclear. We hypothesize that soluble oligomeric forms of Aβ induced RPE degeneration requires the activation of the non-canonical inflammasome pathway.

Methods : Methods:
Oligomeric Aβ was prepared using established protocols. Wild-type (WT) C57BL/6J, Ppif^−/−, Gsdmd^−/−, Casp11^−/− and cGAS^−/− mice received subretinal injections of Aβ^1-40 or Aβ^40-1. RPE degeneration was assessed by fundus photography and Zonula occludens-1 (ZO-1) staining of RPE flat mounts. Primary human RPE cells in culture were exposed to oligomerized Aβ^1-40. Non-canonical Inflammasome activation was monitored by immunoblotting for caspase-1 and caspase-4/11 and quantitative real-time RT-PCR for NLRP3, Gasdermin-D and IL-18

Results : Results:
Subretinal injection of oligomerized Aβ^1-40 peptide induced RPE degeneration in WT but not in Ppif^−/−, Gsdmd^−/−, Casp11^−/− or cGAS^−/− mice. Oligomerized Aβ^1-40 treatment of RPE cells caused activation of Caspase-1 and caspase-4 and induction of Gasdermin-D, IL-18 and NLRP3.

Conclusions : Conclusion:
Our findings reveal the role of the non-canonical imflammsome pathway in Aβ-induced RPE degeneration that could provide potential novel pharmacological targets for the treatment of Geographic Atrophy.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.