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

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of A beta plaques and neurofibrillary tangles, resulting in synaptic loss and 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. Three-dimensional retinal organoids differentiated from human pluripotent stem cells (hPSCs) can effectively model some of the earliest manifestations of disease states, 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 early AD-associated alterations. Results demonstrated the robust differentiation of retinal organoids from both familial AD and unaffected control cell lines, with familial AD retinal organoids exhibiting a significant increase in the A beta 42:A beta 40 ratio as well as phosphorylated Tau protein, characteristic of AD pathology. Further, transcriptional analyses demonstrated the differential expression of many genes and cellular pathways, including those associated with synaptic dysfunction. Taken together, 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.

Automated summary

This study demonstrates the capacity of retinal organoids differentiated from human pluripotent stem cells to effectively model early Alzheimer's disease-related alterations, including the accumulation of A beta plaques and neurofibrillary tangles as well as synaptic dysfunction.