APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types
The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2020
|
| Online Access: | https://hdl.handle.net/1721.1/126369 |
| _version_ | 1811080555110858752 |
|---|---|
| author | Lin, Yuan-Ta Seo, Jinsoo Gao, Fan Feldman, Heather M. Wen, Hsin-Lan Penney, Jay Cam, Hugh P. Gjoneska, Elizabeta Raja, Waseem K Cheng, Jemmie Rueda IV, Richard Kritskiy, Oleg Abdurrob, Fatema Peng, Zhuyu Milo, Blerta Yu, Chung Jong Elmsaouri, Sara Dey, Dilip Chandra Ko, Tak Yankner, Bruce A. Tsai, Li-Huei |
| author2 | Picower Institute for Learning and Memory |
| author_facet | Picower Institute for Learning and Memory Lin, Yuan-Ta Seo, Jinsoo Gao, Fan Feldman, Heather M. Wen, Hsin-Lan Penney, Jay Cam, Hugh P. Gjoneska, Elizabeta Raja, Waseem K Cheng, Jemmie Rueda IV, Richard Kritskiy, Oleg Abdurrob, Fatema Peng, Zhuyu Milo, Blerta Yu, Chung Jong Elmsaouri, Sara Dey, Dilip Chandra Ko, Tak Yankner, Bruce A. Tsai, Li-Huei |
| author_sort | Lin, Yuan-Ta |
| collection | MIT |
| description | The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant. Video Abstract: [Figure presented] By generating and characterizing isogenic APOE3- or APOE4-carrying human brain cell types, Lin et al. show that the APOE4 variant can lead to extensive gene expression alterations, and multiple cellular phenotypes potentially related to AD pathogenesis, in neurons, astrocytes, and microglia. |
| first_indexed | 2024-09-23T11:33:26Z |
| format | Article |
| id | mit-1721.1/126369 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:33:26Z |
| publishDate | 2020 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1263692022-10-01T04:25:17Z APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types Lin, Yuan-Ta Seo, Jinsoo Gao, Fan Feldman, Heather M. Wen, Hsin-Lan Penney, Jay Cam, Hugh P. Gjoneska, Elizabeta Raja, Waseem K Cheng, Jemmie Rueda IV, Richard Kritskiy, Oleg Abdurrob, Fatema Peng, Zhuyu Milo, Blerta Yu, Chung Jong Elmsaouri, Sara Dey, Dilip Chandra Ko, Tak Yankner, Bruce A. Tsai, Li-Huei Picower Institute for Learning and Memory Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant. Video Abstract: [Figure presented] By generating and characterizing isogenic APOE3- or APOE4-carrying human brain cell types, Lin et al. show that the APOE4 variant can lead to extensive gene expression alterations, and multiple cellular phenotypes potentially related to AD pathogenesis, in neurons, astrocytes, and microglia. National Institutes of Health (NIH) (Grants RF1-AG048056, RC1-AG036106, and RF1-AG048029) 2020-07-24T14:26:24Z 2020-07-24T14:26:24Z 2018-05 2018-04 2019-10-09T12:28:45Z Article http://purl.org/eprint/type/JournalArticle 0896-6273 https://hdl.handle.net/1721.1/126369 Lin, Yuan-Ta et al. "APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types." Neuron 98, 6 (June 2018): P1141-1154.e7 © 2018 Elsevier Inc en http://dx.doi.org/10.1016/j.neuron.2018.05.008 Neuron Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | Lin, Yuan-Ta Seo, Jinsoo Gao, Fan Feldman, Heather M. Wen, Hsin-Lan Penney, Jay Cam, Hugh P. Gjoneska, Elizabeta Raja, Waseem K Cheng, Jemmie Rueda IV, Richard Kritskiy, Oleg Abdurrob, Fatema Peng, Zhuyu Milo, Blerta Yu, Chung Jong Elmsaouri, Sara Dey, Dilip Chandra Ko, Tak Yankner, Bruce A. Tsai, Li-Huei APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types |
| title | APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types |
| title_full | APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types |
| title_fullStr | APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types |
| title_full_unstemmed | APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types |
| title_short | APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types |
| title_sort | apoe4 causes widespread molecular and cellular alterations associated with alzheimer s disease phenotypes in human ipsc derived brain cell types |
| url | https://hdl.handle.net/1721.1/126369 |
| work_keys_str_mv | AT linyuanta apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT seojinsoo apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT gaofan apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT feldmanheatherm apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT wenhsinlan apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT penneyjay apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT camhughp apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT gjoneskaelizabeta apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT rajawaseemk apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT chengjemmie apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT ruedaivrichard apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT kritskiyoleg apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT abdurrobfatema apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT pengzhuyu apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT miloblerta apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT yuchungjong apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT elmsaourisara apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT deydilipchandra apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT kotak apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT yanknerbrucea apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes AT tsailihuei apoe4causeswidespreadmolecularandcellularalterationsassociatedwithalzheimersdiseasephenotypesinhumanipscderivedbraincelltypes |