APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation
The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer's disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-β (Aβ) accumulatio...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/138381 |
| _version_ | 1811095431106527232 |
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| author | Lee, Se-In Jeong, Woojin Lim, Heejin Cho, Sukhee Lee, Hyein Jang, Yonghee Cho, Joonho Bae, Simsung Lin, Yuan-Ta Tsai, Li-Huei Moon, Dae Won Seo, Jinsoo |
| author_facet | Lee, Se-In Jeong, Woojin Lim, Heejin Cho, Sukhee Lee, Hyein Jang, Yonghee Cho, Joonho Bae, Simsung Lin, Yuan-Ta Tsai, Li-Huei Moon, Dae Won Seo, Jinsoo |
| author_sort | Lee, Se-In |
| collection | MIT |
| description | The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer's disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-β (Aβ) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal Aβ production. Secretory factors in conditioned media from ApoE4 astrocytes significantly increased amyloid precursor protein (APP) levels and Aβ secretion in neurons. We further found that increased cholesterol secretion from ApoE4 astrocytes was necessary and sufficient to induce the formation of lipid rafts that potentially provide a physical platform for APP localization and facilitate its processing. Our study reveals the contribution of ApoE4 astrocytes to amyloidosis in neurons by expanding lipid rafts and facilitating Aβ production through an oversupply of cholesterol. |
| first_indexed | 2024-09-23T16:16:39Z |
| format | Article |
| id | mit-1721.1/138381 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:16:39Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1383812021-12-09T03:02:06Z APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation Lee, Se-In Jeong, Woojin Lim, Heejin Cho, Sukhee Lee, Hyein Jang, Yonghee Cho, Joonho Bae, Simsung Lin, Yuan-Ta Tsai, Li-Huei Moon, Dae Won Seo, Jinsoo The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer's disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-β (Aβ) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal Aβ production. Secretory factors in conditioned media from ApoE4 astrocytes significantly increased amyloid precursor protein (APP) levels and Aβ secretion in neurons. We further found that increased cholesterol secretion from ApoE4 astrocytes was necessary and sufficient to induce the formation of lipid rafts that potentially provide a physical platform for APP localization and facilitate its processing. Our study reveals the contribution of ApoE4 astrocytes to amyloidosis in neurons by expanding lipid rafts and facilitating Aβ production through an oversupply of cholesterol. 2021-12-08T16:57:29Z 2021-12-08T16:57:29Z 2021-09 2021-12-08T16:55:31Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/138381 Lee, Se-In, Jeong, Woojin, Lim, Heejin, Cho, Sukhee, Lee, Hyein et al. 2021. "APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation." Stem Cell Reports, 16 (9). en 10.1016/j.stemcr.2021.07.017 Stem Cell Reports Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Lee, Se-In Jeong, Woojin Lim, Heejin Cho, Sukhee Lee, Hyein Jang, Yonghee Cho, Joonho Bae, Simsung Lin, Yuan-Ta Tsai, Li-Huei Moon, Dae Won Seo, Jinsoo APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation |
| title | APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation |
| title_full | APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation |
| title_fullStr | APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation |
| title_full_unstemmed | APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation |
| title_short | APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation |
| title_sort | apoe4 carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and aβ generation |
| url | https://hdl.handle.net/1721.1/138381 |
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