Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes
The dismal success rate of clinical trials for Alzheimer’s disease (AD) motivates us to develop model systems of AD pathology that have higher predictive validity. The advent of induced pluripotent stem cells (iPSCs) allows us to model pathology and study disease mechanisms directly in human neural...
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2017
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| Online Access: | http://hdl.handle.net/1721.1/106315 https://orcid.org/0000-0002-5452-2352 https://orcid.org/0000-0002-2461-1135 https://orcid.org/0000-0003-1262-0592 |
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| author | Raja, Waseem K Mungenast, Alison Lin, Yuan-Ta Ko, Tak Abdurrob, Fatema Seo, Jinsoo Tsai, Li-Huei |
| author2 | Picower Institute for Learning and Memory |
| author_facet | Picower Institute for Learning and Memory Raja, Waseem K Mungenast, Alison Lin, Yuan-Ta Ko, Tak Abdurrob, Fatema Seo, Jinsoo Tsai, Li-Huei |
| author_sort | Raja, Waseem K |
| collection | MIT |
| description | The dismal success rate of clinical trials for Alzheimer’s disease (AD) motivates us to develop model systems of AD pathology that have higher predictive validity. The advent of induced pluripotent stem cells (iPSCs) allows us to model pathology and study disease mechanisms directly in human neural cells from healthy individual as well as AD patients. However, two-dimensional culture systems do not recapitulate the complexity of neural tissue, and phenotypes such as extracellular protein aggregation are difficult to observe. We report brain organoids that use pluripotent stem cells derived from AD patients and recapitulate AD-like pathologies such as amyloid aggregation, hyperphosphorylated tau protein, and endosome abnormalities. These pathologies are observed in an age-dependent manner in organoids derived from multiple familial AD (fAD) patients harboring amyloid precursor protein (APP) duplication or presenilin1 (PSEN1) mutation, compared to controls. The incidence of AD pathology was consistent amongst several fAD lines, which carried different mutations. Although these are complex assemblies of neural tissue, they are also highly amenable to experimental manipulation. We find that treatment of patient-derived organoids with β- and γ-secretase inhibitors significantly reduces amyloid and tau pathology. Moreover, these results show the potential of this model system to greatly increase the translatability of pre-clinical drug discovery in AD. |
| first_indexed | 2024-09-23T15:45:45Z |
| format | Article |
| id | mit-1721.1/106315 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:45:45Z |
| publishDate | 2017 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/1063152022-09-29T15:59:43Z Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes Raja, Waseem K Mungenast, Alison Lin, Yuan-Ta Ko, Tak Abdurrob, Fatema Seo, Jinsoo Tsai, Li-Huei Picower Institute for Learning and Memory Raja, Waseem K Mungenast, Alison Lin, Yuan-Ta Ko, Tak Abdurrob, Fatema Seo, Jinsoo Tsai, Li-Huei The dismal success rate of clinical trials for Alzheimer’s disease (AD) motivates us to develop model systems of AD pathology that have higher predictive validity. The advent of induced pluripotent stem cells (iPSCs) allows us to model pathology and study disease mechanisms directly in human neural cells from healthy individual as well as AD patients. However, two-dimensional culture systems do not recapitulate the complexity of neural tissue, and phenotypes such as extracellular protein aggregation are difficult to observe. We report brain organoids that use pluripotent stem cells derived from AD patients and recapitulate AD-like pathologies such as amyloid aggregation, hyperphosphorylated tau protein, and endosome abnormalities. These pathologies are observed in an age-dependent manner in organoids derived from multiple familial AD (fAD) patients harboring amyloid precursor protein (APP) duplication or presenilin1 (PSEN1) mutation, compared to controls. The incidence of AD pathology was consistent amongst several fAD lines, which carried different mutations. Although these are complex assemblies of neural tissue, they are also highly amenable to experimental manipulation. We find that treatment of patient-derived organoids with β- and γ-secretase inhibitors significantly reduces amyloid and tau pathology. Moreover, these results show the potential of this model system to greatly increase the translatability of pre-clinical drug discovery in AD. 2017-01-10T14:41:33Z 2017-01-10T14:41:33Z 2016-09 2016-05 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/106315 Raja, Waseem K. et al. “Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes.” Ed. Jaya Padmanabhan. PLOS ONE 11.9 (2016): e0161969. https://orcid.org/0000-0002-5452-2352 https://orcid.org/0000-0002-2461-1135 https://orcid.org/0000-0003-1262-0592 en_US http://dx.doi.org/10.1371/journal.pone.0161969 PLOS ONE Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science PLOS |
| spellingShingle | Raja, Waseem K Mungenast, Alison Lin, Yuan-Ta Ko, Tak Abdurrob, Fatema Seo, Jinsoo Tsai, Li-Huei Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes |
| title | Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes |
| title_full | Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes |
| title_fullStr | Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes |
| title_full_unstemmed | Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes |
| title_short | Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer’s Disease Phenotypes |
| title_sort | self organizing 3d human neural tissue derived from induced pluripotent stem cells recapitulate alzheimer s disease phenotypes |
| url | http://hdl.handle.net/1721.1/106315 https://orcid.org/0000-0002-5452-2352 https://orcid.org/0000-0002-2461-1135 https://orcid.org/0000-0003-1262-0592 |
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