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APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids
BACKGROUND: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer’s disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. M...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10441762/ https://www.ncbi.nlm.nih.gov/pubmed/37605285 http://dx.doi.org/10.1186/s13287-023-03444-y |
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author | Zhao, Jing Ikezu, Tadafumi C. Lu, Wenyan Macyczko, Jesse R. Li, Yonghe Lewis-Tuffin, Laura J. Martens, Yuka A. Ren, Yingxue Zhu, Yiyang Asmann, Yan W. Ertekin-Taner, Nilüfer Kanekiyo, Takahisa Bu, Guojun |
author_facet | Zhao, Jing Ikezu, Tadafumi C. Lu, Wenyan Macyczko, Jesse R. Li, Yonghe Lewis-Tuffin, Laura J. Martens, Yuka A. Ren, Yingxue Zhu, Yiyang Asmann, Yan W. Ertekin-Taner, Nilüfer Kanekiyo, Takahisa Bu, Guojun |
author_sort | Zhao, Jing |
collection | PubMed |
description | BACKGROUND: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer’s disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. METHODS: We generated three-dimensional (3-D) cerebral organoids from human parental iPSC lines and its isogenic APOE-deficient (APOE(−/−)) iPSC line. To elucidate the cell-type-specific effects of APOE deficiency in the cerebral organoids, we performed scRNA-seq in the parental and APOE(−/−) cerebral organoids at Day 90. RESULTS: We show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single-cell RNA sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the eukaryotic initiation factor 2 (EIF2) signaling pathway as these events were alleviated by the treatment of an integrated stress response inhibitor (ISRIB). APOE deletion also leads to activation of the Wnt/β-catenin signaling pathway with concomitant decrease of secreted frizzled-related protein 1 (SFRP1) expression in glia cells. Importantly, the critical role of apoE in cell-type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3. CONCLUSIONS: Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-023-03444-y. |
format | Online Article Text |
id | pubmed-10441762 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-104417622023-08-22 APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids Zhao, Jing Ikezu, Tadafumi C. Lu, Wenyan Macyczko, Jesse R. Li, Yonghe Lewis-Tuffin, Laura J. Martens, Yuka A. Ren, Yingxue Zhu, Yiyang Asmann, Yan W. Ertekin-Taner, Nilüfer Kanekiyo, Takahisa Bu, Guojun Stem Cell Res Ther Research BACKGROUND: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer’s disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. METHODS: We generated three-dimensional (3-D) cerebral organoids from human parental iPSC lines and its isogenic APOE-deficient (APOE(−/−)) iPSC line. To elucidate the cell-type-specific effects of APOE deficiency in the cerebral organoids, we performed scRNA-seq in the parental and APOE(−/−) cerebral organoids at Day 90. RESULTS: We show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single-cell RNA sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the eukaryotic initiation factor 2 (EIF2) signaling pathway as these events were alleviated by the treatment of an integrated stress response inhibitor (ISRIB). APOE deletion also leads to activation of the Wnt/β-catenin signaling pathway with concomitant decrease of secreted frizzled-related protein 1 (SFRP1) expression in glia cells. Importantly, the critical role of apoE in cell-type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3. CONCLUSIONS: Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-023-03444-y. BioMed Central 2023-08-21 /pmc/articles/PMC10441762/ /pubmed/37605285 http://dx.doi.org/10.1186/s13287-023-03444-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Zhao, Jing Ikezu, Tadafumi C. Lu, Wenyan Macyczko, Jesse R. Li, Yonghe Lewis-Tuffin, Laura J. Martens, Yuka A. Ren, Yingxue Zhu, Yiyang Asmann, Yan W. Ertekin-Taner, Nilüfer Kanekiyo, Takahisa Bu, Guojun APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids |
title | APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids |
title_full | APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids |
title_fullStr | APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids |
title_full_unstemmed | APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids |
title_short | APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids |
title_sort | apoe deficiency impacts neural differentiation and cholesterol biosynthesis in human ipsc-derived cerebral organoids |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10441762/ https://www.ncbi.nlm.nih.gov/pubmed/37605285 http://dx.doi.org/10.1186/s13287-023-03444-y |
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