Abstract: Frontotemporal dementia is an early-onset neurodegenerative disorder characterized by progressive neuronal loss, often associated with hereditary mutations in the MAPT gene, which encodes the tau protein. Patients with Alzheimer’s disease and FTD exhibit retinal defects, including changes in retinal thickness and the accumulation of hyperphosphorylated tau aggregates, which correlate with disease severity. The retina's accessibility for non-invasive imaging makes it an ideal model for studying disease progression and evaluating potential therapeutic interventions in real-time. A key gap in current research is the limited understanding of tau's role in neurodegeneration. The link between neurodevelopment and neurodegeneration has already been proposed for iPSC-derived cortical cultures and mouse models. To address this gap, we explored the involvement of tau in retinal development and maturation using two isogenic iPSC lines differing in the presence of the MAPT IVS10+16 mutation, which is linked to FTD. We generated 2D retinal cultures and 3D retinal organoids to investigate the effects of this mutation. Our findings reveal that tau-mutant retinal cultures, at later differentiation stages, exhibit abnormal tau isoform expression, increased tau phosphorylation, and toxic tau aggregates, indicative of early pathological tau accumulation. Functionally, we observed impaired synaptic maturation, reduced network synchronization, and elevated markers of cellular stress. At earlier differentiation stages, tau-mutant cultures displayed delays in neural rosette formation, impairing differentiation, and maturation of retinal progenitor cells, accompanied by a reduced number of mitochondria. This developmental delay extended to retinal organoids, where optic vesicle structures were smaller, and the neuronal retina exhibited disorganized morphology. These results demonstrate that the MAPT IVS10+16 mutation disrupts human retinal neurogenesis, leading to both developmental deficits and early tau pathology. By establishing an iPSC-derived retinal model for tauopathy research, this study provides a novel platform to investigate the neurodevelopmental aspects of FTD and related disorders, offering a fresh perspective on tauopathies before the onset of full-blown neurodegeneration.
