Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models

The generation of retinal models from human induced pluripotent stem cells holds significant potential for advancing our understanding of retinal development, neurodegeneration, and the in vitro modeling of neurodegenerative disorders. The retina, as an accessible part of the central nervous system, offers a unique window into these processes, making it invaluable for both study and early diagnosis. This study investigates the impact of the Frontotemporal Dementia-linked IVS 10 + 16 MAPT mutation on retinal development and function using 2D and 3D retinal models derived from human induced pluripotent stem cells. Our findings reveal that the MAPT mutation leads to delayed retinal cell differentiation and maturation, with tau-mutant disease models exhibiting sustained higher expression of retinal progenitor cell markers and a reduced presence of post-mitotic neurons. Both 2D and 3D tau-mutant retinal models demonstrated an imbalance in tau isoforms, favoring 4R tau, along with increased tau phosphorylation, altered neurite morphology, and impaired cytoskeletal maturation. These changes are associated with impaired synaptic development, reduced neuronal connectivity, and enhanced cellular stress responses, including the increased formation of stress granules, markers of apoptosis and autophagy, and the presence of intracellular toxic tau aggregates. This study highlights the value of retinal models derived from human induced pluripotent stem cells in exploring the mechanisms underlying retinal pathology associated with tau mutations. These models offer essential insights into the development of therapeutic strategies for neurodegenerative diseases characterized by tau aggregation.