Modeling retinal Alzheimer’s disease histopathology with human iPSC-derived retinal organoids

Abstract

Purpose : Alzheimer’s disease (AD) is a complex multifactorial disease that affects 33 to 38 million people worldwide, causing irreversible damage to the central nervous system. In the eye, the retinal phenotype is consistent with the brain histopathology, including the presence of beta-amyloid (Aß) plaques and intracellular neurofibrillary tangles (NFT) of abnormally phosphorylated Tau proteins (pTau). Unfortunately, no treatment exists to cure this disease. Thus, we set out to develop and characterize the first hiPSC-derived organoid model of retinal AD histopathology that can be used for the validation of potential therapeutic drugs.

Methods : hiPSC from 3 wild type (WT) and 2 familial AD (fAD) donors were used to generate retinal organoids (RO) using the Zhong et al. (2014) protocol. The cellular composition and histopathological hallmarks of AD were assessed at 6 months of differentiation by Western blot, immunofluorescence staining for retinal cell type-markers as well as Aβ and pathological pTau forms, and by NIAD-4 staining for amyloid plaques. Quantification was performed using FIJI software for 2D images and 3D-ARQ for whole mount ROs.

Results : AD-ROs are similar to WT-ROs in cellular composition and structure. However, pathological pTau staining and Aß deposits are significantly increased in AD-ROs compared to WT-ROs. Finally, we developed a quantitative, high-throughput assay for plaque detection that is amenable to translational research applications.

Conclusions : Our AD-RO models mimic the histopathology of the human AD retina and constitute valuable tools for the screening and validation of candidate molecules with therapeutic potential.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.