Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization
For the past 20 years, the majority of cell culture studies reported that increasing cholesterol level increases amyloid-β (Aβ) production. Conversely, other studies and genetic evidences support that cellular cholesterol loss leads to Aβ generation. As a highly controversial issue in Alzheimer’s di...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227523000408 |
| _version_ | 1797822111506497536 |
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| author | Yue Huang Wenbin Zhang Xiaorou Guo Ying Zhang Junfeng Wu Hengbing Zu |
| author_facet | Yue Huang Wenbin Zhang Xiaorou Guo Ying Zhang Junfeng Wu Hengbing Zu |
| author_sort | Yue Huang |
| collection | DOAJ |
| description | For the past 20 years, the majority of cell culture studies reported that increasing cholesterol level increases amyloid-β (Aβ) production. Conversely, other studies and genetic evidences support that cellular cholesterol loss leads to Aβ generation. As a highly controversial issue in Alzheimer’s disease pathogenesis, the apparent contradiction prompted us to again explore the role of cellular cholesterol in Aβ production. Here, we adopted new neuronal and astrocytic cell models induced by 3β-hydroxysterol-Δ24 reductase (DHCR24), which obviously differ from the widely used cell models with overexpressing amyloid precursor protein (APP) in the majority of previous studies. In neuronal and astrocytic cell model, we found that deficiency of cellular cholesterol by DHCR24 knockdown obviously increased intracellular and extracellular Aβ generation. Importantly, in cell models with overexpressing APP, we found that APP overexpression could disrupt cellular cholesterol homeostasis and affect function of cells, coupled with the increase of APP β-cleavage product, 99-residue transmembrane C-terminal domain. Therefore, we suppose the results derived from the APP knockin models will need to be re-evaluated. One rational explanation for the discrepancy between our outcomes and the previous studies could be attributed to the two different cell models. Mechanistically, we showed that cellular cholesterol loss obviously altered APP intracellular localization by affecting cholesterol-related trafficking protein of APP. Therefore, our outcomes strongly support cellular cholesterol loss by DHCR24 knockdown leads to Aβ production. |
| first_indexed | 2024-03-13T10:03:04Z |
| format | Article |
| id | doaj.art-495718290d0a4da39724cd92933bf584 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-03-13T10:03:04Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-495718290d0a4da39724cd92933bf5842023-05-23T04:20:36ZengElsevierJournal of Lipid Research0022-22752023-05-01645100367Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localizationYue Huang0Wenbin Zhang1Xiaorou Guo2Ying Zhang3Junfeng Wu4Hengbing Zu5Department of Neurology, Jinshan Hospital Affiliated to Fudan University, Shanghai, ChinaDepartment of Neurology, Jinshan Hospital Affiliated to Fudan University, Shanghai, ChinaDepartment of Neurology, Jinshan Hospital Affiliated to Fudan University, Shanghai, ChinaDepartment of Neurology, Jinshan Hospital Affiliated to Fudan University, Shanghai, ChinaFor correspondence: Hengbing Zu; Junfeng Wu; Department of Neurology, Jinshan Hospital Affiliated to Fudan University, Shanghai, ChinaFor correspondence: Hengbing Zu; Junfeng Wu; Department of Neurology, Jinshan Hospital Affiliated to Fudan University, Shanghai, ChinaFor the past 20 years, the majority of cell culture studies reported that increasing cholesterol level increases amyloid-β (Aβ) production. Conversely, other studies and genetic evidences support that cellular cholesterol loss leads to Aβ generation. As a highly controversial issue in Alzheimer’s disease pathogenesis, the apparent contradiction prompted us to again explore the role of cellular cholesterol in Aβ production. Here, we adopted new neuronal and astrocytic cell models induced by 3β-hydroxysterol-Δ24 reductase (DHCR24), which obviously differ from the widely used cell models with overexpressing amyloid precursor protein (APP) in the majority of previous studies. In neuronal and astrocytic cell model, we found that deficiency of cellular cholesterol by DHCR24 knockdown obviously increased intracellular and extracellular Aβ generation. Importantly, in cell models with overexpressing APP, we found that APP overexpression could disrupt cellular cholesterol homeostasis and affect function of cells, coupled with the increase of APP β-cleavage product, 99-residue transmembrane C-terminal domain. Therefore, we suppose the results derived from the APP knockin models will need to be re-evaluated. One rational explanation for the discrepancy between our outcomes and the previous studies could be attributed to the two different cell models. Mechanistically, we showed that cellular cholesterol loss obviously altered APP intracellular localization by affecting cholesterol-related trafficking protein of APP. Therefore, our outcomes strongly support cellular cholesterol loss by DHCR24 knockdown leads to Aβ production.http://www.sciencedirect.com/science/article/pii/S0022227523000408Alzheimer’s diseaseAPPAmyloid-βDHCR24CholesterolPathogenesis |
| spellingShingle | Yue Huang Wenbin Zhang Xiaorou Guo Ying Zhang Junfeng Wu Hengbing Zu Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization Journal of Lipid Research Alzheimer’s disease APP Amyloid-β DHCR24 Cholesterol Pathogenesis |
| title | Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization |
| title_full | Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization |
| title_fullStr | Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization |
| title_full_unstemmed | Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization |
| title_short | Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization |
| title_sort | cellular cholesterol loss by dhcr24 knockdown leads to aβ production by changing app intracellular localization |
| topic | Alzheimer’s disease APP Amyloid-β DHCR24 Cholesterol Pathogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S0022227523000408 |
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