Development of a three-dimensional organoid model to explore early retinal phenotypes associated with Alzheimer’s disease

Abstract

Purpose : Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of Aβ plaques and neurofibrillary tangles, resulting in neurodegeneration. The retina is an extension of the central nervous system within the eye, sharing many structural similarities with the brain, and previous studies have observed AD-related phenotypes within the retina. Human pluripotent stem cells (hPSCs) can effectively model some of the earliest manifestations of disease states, including those affecting the retina, yet early AD-associated phenotypes have not yet been examined. Thus, the current study focused upon the differentiation of hPSCs into retinal organoids for the analysis of AD-associated alterations.

Methods : hPSCs from both AD as well as healthy controls were used in all studies, and their pluripotency as well as the presence or absence of AD-associated gene variants was validated. Subsequently, cell lines were directed to differentiate to yield retinal organoids following established methods. Upon acquisition of retinal organoids, we assesed for characteristic features of AD pathology, including changes in the levels of pathological Aβ42 as well as phosphorylated tau protein. Retinal organoids with AD-associated mutations were then transcriptionally profiled to further identify other alterations that may be leveraged as early indicators of AD pathology.

Results : Results demonstrated the robust differentiation of retinal organoids from both familial AD and unaffected control cell lines. AD retinal organoids also exhibited characteristic pathological features, including an elevation in the Aβ42:Aβ40 ratio in conditioned medium, as well as a significant increase in pTau protein in AD retinal organoids. Transcriptional analyses further demonstrated the differential expression of many genes and cellular pathways, particularly those associated with synaptic dysfunction.

Conclusions : The current study demonstrates the ability of retinal organoids to serve as a powerful model for the identification of some of the earliest retinal alterations associated with AD, thereby validating the potential use of retinal organoids as a model system to explore early alterations within an easily accessible region of the central nervous system, along with important implications for the early diagnosis of AD.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.