A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration
We describe the construction and phenotypic analysis of a human embryonic stem cell model of progressive Aβ-dependent neurodegeneration (ND) with potential relevance to Alzheimer’s disease (AD). We modified one allele of the normal APP locus to directly express a secretory form of Aβ40 or Aβ42, enab...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.01007/full |
| _version_ | 1818317698487025664 |
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| author | Teresa Ubina Teresa Ubina Martha Magallanes Saumya Srivastava Charles D. Warden Jiing-Kuan Yee Jiing-Kuan Yee Paul M. Salvaterra Paul M. Salvaterra |
| author_facet | Teresa Ubina Teresa Ubina Martha Magallanes Saumya Srivastava Charles D. Warden Jiing-Kuan Yee Jiing-Kuan Yee Paul M. Salvaterra Paul M. Salvaterra |
| author_sort | Teresa Ubina |
| collection | DOAJ |
| description | We describe the construction and phenotypic analysis of a human embryonic stem cell model of progressive Aβ-dependent neurodegeneration (ND) with potential relevance to Alzheimer’s disease (AD). We modified one allele of the normal APP locus to directly express a secretory form of Aβ40 or Aβ42, enabling expression from this edited allele to bypass the normal amyloidogenic APP processing pathway. Following neuronal differentiation, edited cell lines specifically accumulate intracellular aggregated/oligomeric Aβ, exhibit a synaptic deficit, and have an abnormal accumulation of endolysosomal vesicles. Edited cultures progress to a stage of overt ND. All phenotypes appear at earlier culture times for Aβ42 relative to Aβ40. Whole transcriptome RNA-Seq analysis identified 23 up and 70 down regulated genes (differentially expressed genes) with similar directional fold change but larger absolute values in the Aβ42 samples suggesting common underlying pathogenic mechanisms. Pathway/annotation analysis suggested that down regulation of extracellular matrix and cilia functions is significantly overrepresented. This cellular model could be useful for uncovering mechanisms directly linking Aβ to neuronal death and as a tool to screen for new therapeutic agents that slow or prevent human ND. |
| first_indexed | 2024-12-13T09:41:28Z |
| format | Article |
| id | doaj.art-2ecfb927a97d47458e1f4fbdfa44373b |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-13T09:41:28Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-2ecfb927a97d47458e1f4fbdfa44373b2022-12-21T23:52:10ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-09-011310.3389/fnins.2019.01007473973A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive NeurodegenerationTeresa Ubina0Teresa Ubina1Martha Magallanes2Saumya Srivastava3Charles D. Warden4Jiing-Kuan Yee5Jiing-Kuan Yee6Paul M. Salvaterra7Paul M. Salvaterra8Department of Developmental and Stem Cell Biology, Beckman Research Institute – City of Hope, Duarte, CA, United StatesDepartment of Biology, California State University, San Bernardino, San Bernardino, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute – City of Hope, Duarte, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute – City of Hope, Duarte, CA, United StatesIntegrative Genomics Core, Beckman Research Institute – City of Hope, Duarte, CA, United StatesDepartment of Diabetes, Beckman Research Institute – City of Hope, Duarte, CA, United StatesIrell and Manella Graduate School of Biological Sciences, Beckman Research Institute – City of Hope, Duarte, CA, United StatesDepartment of Developmental and Stem Cell Biology, Beckman Research Institute – City of Hope, Duarte, CA, United StatesIrell and Manella Graduate School of Biological Sciences, Beckman Research Institute – City of Hope, Duarte, CA, United StatesWe describe the construction and phenotypic analysis of a human embryonic stem cell model of progressive Aβ-dependent neurodegeneration (ND) with potential relevance to Alzheimer’s disease (AD). We modified one allele of the normal APP locus to directly express a secretory form of Aβ40 or Aβ42, enabling expression from this edited allele to bypass the normal amyloidogenic APP processing pathway. Following neuronal differentiation, edited cell lines specifically accumulate intracellular aggregated/oligomeric Aβ, exhibit a synaptic deficit, and have an abnormal accumulation of endolysosomal vesicles. Edited cultures progress to a stage of overt ND. All phenotypes appear at earlier culture times for Aβ42 relative to Aβ40. Whole transcriptome RNA-Seq analysis identified 23 up and 70 down regulated genes (differentially expressed genes) with similar directional fold change but larger absolute values in the Aβ42 samples suggesting common underlying pathogenic mechanisms. Pathway/annotation analysis suggested that down regulation of extracellular matrix and cilia functions is significantly overrepresented. This cellular model could be useful for uncovering mechanisms directly linking Aβ to neuronal death and as a tool to screen for new therapeutic agents that slow or prevent human ND.https://www.frontiersin.org/article/10.3389/fnins.2019.01007/fullamyloid-betaneurodegenerationstem cellsAlzheimer’s diseaseAlzheimer’s model |
| spellingShingle | Teresa Ubina Teresa Ubina Martha Magallanes Saumya Srivastava Charles D. Warden Jiing-Kuan Yee Jiing-Kuan Yee Paul M. Salvaterra Paul M. Salvaterra A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration Frontiers in Neuroscience amyloid-beta neurodegeneration stem cells Alzheimer’s disease Alzheimer’s model |
| title | A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration |
| title_full | A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration |
| title_fullStr | A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration |
| title_full_unstemmed | A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration |
| title_short | A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration |
| title_sort | human embryonic stem cell model of aβ dependent chronic progressive neurodegeneration |
| topic | amyloid-beta neurodegeneration stem cells Alzheimer’s disease Alzheimer’s model |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.01007/full |
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