Exploring Neurotoxic Effects of Extracellular Tau Fibrils on iPSC-Derived Retinal Neurons.

Tau fibrils, abnormal aggregates of the tau protein associated with neurodegenerative diseases, disrupt neuronal function and are primarily linked to brain pathology. However, evidence suggests their presence in the retina, sparking interest in their potential as a model for studying neurodegeneration and as a biomarker for disease diagnosis and progression. This study explores their presence in the retina, proposing it as a model for neurodegeneration research and a potential biomarker for disease. We focused on tau fragment K18, a truncated tau form with high binding and aggregation properties. Fibrillation of this fragment was induced with heparin to generate oligomers or medium-length fibrils. Retinal neurons were differentiated from human iPSCs to study the impact of extracellular tau oligomers and fibrils in a controlled environment. Assessing tau seed uptake and concentration, we performed tau k18 seeding and collected samples after 1 and 15 days for immunofluorescence analysis. Results showed an increased Cleaved-casp3 positive nuclei in our cultures treated for 15-days, and an alteration in cytoskeleton markers suggested a correlation between tau fibrils exposure and cellular damage. Neurotoxicity effect of tau seeds was also confirmed by live/dead assay. We concluded that tau fibrils induced cellular stress, disrupted neuronal function, and caused cell death in iPSC-derived retinal neurons. In summary, tau fibrils in the retina represent a burgeoning area of research with potential implications for understanding neurodegenerative diseases. They offer insights into disease mechanisms, diagnostic possibilities, and therapeutic monitoring. The in vitro models developed serve as a valuable tool for investigating the consequences of tau pathology on retinal cells, providing a foundation for exploring interventions to protect retinal health.