Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models
Abstract 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 nervou...
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| Format: | Article |
| Language: | English |
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BMC
2025-01-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-024-01920-x |
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| author | Lorenza Mautone Federica Cordella Alessandro Soloperto Silvia Ghirga Giorgia Di Gennaro Ylenia Gigante Silvia Di Angelantonio |
| author_facet | Lorenza Mautone Federica Cordella Alessandro Soloperto Silvia Ghirga Giorgia Di Gennaro Ylenia Gigante Silvia Di Angelantonio |
| author_sort | Lorenza Mautone |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-48274725849841269531ad584dd3dd83 |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-48274725849841269531ad584dd3dd832025-02-02T12:47:07ZengBMCActa Neuropathologica Communications2051-59602025-01-0113112110.1186/s40478-024-01920-xUnderstanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal modelsLorenza Mautone0Federica Cordella1Alessandro Soloperto2Silvia Ghirga3Giorgia Di Gennaro4Ylenia Gigante5Silvia Di Angelantonio6Department of Physiology and Pharmacology, Sapienza University of RomeDepartment of Physiology and Pharmacology, Sapienza University of RomeCenter for Life Nano- & Neuro-Science, Istituto Italiano di TecnologiaCenter for Life Nano- & Neuro-Science, Istituto Italiano di TecnologiaDepartment of Physiology and Pharmacology, Sapienza University of RomeCenter for Life Nano- & Neuro-Science, Istituto Italiano di TecnologiaDepartment of Physiology and Pharmacology, Sapienza University of RomeAbstract 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.https://doi.org/10.1186/s40478-024-01920-xRetinaNeurodevelopmentNeurodegenerationInduced pluripotent stem cellsTauPhospho-tau |
| spellingShingle | Lorenza Mautone Federica Cordella Alessandro Soloperto Silvia Ghirga Giorgia Di Gennaro Ylenia Gigante Silvia Di Angelantonio Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models Acta Neuropathologica Communications Retina Neurodevelopment Neurodegeneration Induced pluripotent stem cells Tau Phospho-tau |
| title | Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models |
| title_full | Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models |
| title_fullStr | Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models |
| title_full_unstemmed | Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models |
| title_short | Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models |
| title_sort | understanding retinal tau pathology through functional 2d and 3d ipsc derived in vitro retinal models |
| topic | Retina Neurodevelopment Neurodegeneration Induced pluripotent stem cells Tau Phospho-tau |
| url | https://doi.org/10.1186/s40478-024-01920-x |
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