ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis
The strongest genetic risk factor for sporadic Alzheimer’s disease (AD) is the presence of the ε4 allele of the apolipoprotein E (ApoE) gene, the major apolipoprotein involved in brain cholesterol homeostasis. Being astrocytes the main producers of cholesterol and ApoE in the brain, we investigated...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/11/2168 |
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| author | Erica Staurenghi Valerio Leoni Marco Lo Iacono Barbara Sottero Gabriella Testa Serena Giannelli Gabriella Leonarduzzi Paola Gamba |
| author_facet | Erica Staurenghi Valerio Leoni Marco Lo Iacono Barbara Sottero Gabriella Testa Serena Giannelli Gabriella Leonarduzzi Paola Gamba |
| author_sort | Erica Staurenghi |
| collection | DOAJ |
| description | The strongest genetic risk factor for sporadic Alzheimer’s disease (AD) is the presence of the ε4 allele of the apolipoprotein E (ApoE) gene, the major apolipoprotein involved in brain cholesterol homeostasis. Being astrocytes the main producers of cholesterol and ApoE in the brain, we investigated the impact of the ApoE genotype on astrocyte cholesterol homeostasis. Two mouse astrocytic cell lines expressing the human ApoE3 or ApoE4 isoform were employed. Gas chromatography–mass spectrometry (GC-MS) analysis pointed out that the levels of total cholesterol, cholesterol precursors, and various oxysterols are altered in ApoE4 astrocytes. Moreover, the gene expression analysis of more than 40 lipid-related genes by qRT-PCR showed that certain genes are up-regulated (e.g., CYP27A1) and others down-regulated (e.g., PPARγ, LXRα) in ApoE4, compared to ApoE3 astrocytes. Beyond confirming the significant reduction in the levels of PPARγ, a key transcription factor involved in the maintenance of lipid homeostasis, Western blotting showed that both intracellular and secreted ApoE levels are altered in ApoE4 astrocytes, as well as the levels of receptors and transporters involved in lipid uptake/efflux (ABCA1, LDLR, LRP1, and ApoER2). Data showed that the ApoE genotype clearly affects astrocytic cholesterol homeostasis; however, further investigation is needed to clarify the mechanisms underlying these differences and the consequences on neighboring cells. Indeed, drug development aimed at restoring cholesterol homeostasis could be a potential strategy to counteract AD. |
| first_indexed | 2024-03-09T19:19:20Z |
| format | Article |
| id | doaj.art-b095b2435a404d40ac4eda8ffadbc6ae |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T19:19:20Z |
| publishDate | 2022-11-01 |
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| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-b095b2435a404d40ac4eda8ffadbc6ae2023-11-24T03:30:19ZengMDPI AGAntioxidants2076-39212022-11-011111216810.3390/antiox11112168ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol HomeostasisErica Staurenghi0Valerio Leoni1Marco Lo Iacono2Barbara Sottero3Gabriella Testa4Serena Giannelli5Gabriella Leonarduzzi6Paola Gamba7Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyLaboratory of Clinical Biochemistry, Hospital Pius XI of Desio, ASST-Brianza, University of Milano-Bicocca, 20126 Monza, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyThe strongest genetic risk factor for sporadic Alzheimer’s disease (AD) is the presence of the ε4 allele of the apolipoprotein E (ApoE) gene, the major apolipoprotein involved in brain cholesterol homeostasis. Being astrocytes the main producers of cholesterol and ApoE in the brain, we investigated the impact of the ApoE genotype on astrocyte cholesterol homeostasis. Two mouse astrocytic cell lines expressing the human ApoE3 or ApoE4 isoform were employed. Gas chromatography–mass spectrometry (GC-MS) analysis pointed out that the levels of total cholesterol, cholesterol precursors, and various oxysterols are altered in ApoE4 astrocytes. Moreover, the gene expression analysis of more than 40 lipid-related genes by qRT-PCR showed that certain genes are up-regulated (e.g., CYP27A1) and others down-regulated (e.g., PPARγ, LXRα) in ApoE4, compared to ApoE3 astrocytes. Beyond confirming the significant reduction in the levels of PPARγ, a key transcription factor involved in the maintenance of lipid homeostasis, Western blotting showed that both intracellular and secreted ApoE levels are altered in ApoE4 astrocytes, as well as the levels of receptors and transporters involved in lipid uptake/efflux (ABCA1, LDLR, LRP1, and ApoER2). Data showed that the ApoE genotype clearly affects astrocytic cholesterol homeostasis; however, further investigation is needed to clarify the mechanisms underlying these differences and the consequences on neighboring cells. Indeed, drug development aimed at restoring cholesterol homeostasis could be a potential strategy to counteract AD.https://www.mdpi.com/2076-3921/11/11/2168astrocytesalzheimer’s diseaseapolipoprotein EApoE4cholesterol metabolismlipids |
| spellingShingle | Erica Staurenghi Valerio Leoni Marco Lo Iacono Barbara Sottero Gabriella Testa Serena Giannelli Gabriella Leonarduzzi Paola Gamba ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis Antioxidants astrocytes alzheimer’s disease apolipoprotein E ApoE4 cholesterol metabolism lipids |
| title | ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis |
| title_full | ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis |
| title_fullStr | ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis |
| title_full_unstemmed | ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis |
| title_short | ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis |
| title_sort | apoe3 vs apoe4 astrocytes a detailed analysis provides new insights into differences in cholesterol homeostasis |
| topic | astrocytes alzheimer’s disease apolipoprotein E ApoE4 cholesterol metabolism lipids |
| url | https://www.mdpi.com/2076-3921/11/11/2168 |
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