DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice
Abstract Accumulating evidences reveal that cellular cholesterol deficiency could trigger the onset of Alzheimer’s disease (AD). As a key regulator, 24-dehydrocholesterol reductase (DHCR24) controls cellular cholesterol homeostasis, which was found to be downregulated in AD vulnerable regions and in...
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| Format: | Article |
| Language: | English |
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BMC
2023-06-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01593-y |
| _version_ | 1797795465126739968 |
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| author | Wen-bin Zhang Yue Huang Xiao-rou Guo Meng-qi Zhang Xiang-shan Yuan Heng-bing Zu |
| author_facet | Wen-bin Zhang Yue Huang Xiao-rou Guo Meng-qi Zhang Xiang-shan Yuan Heng-bing Zu |
| author_sort | Wen-bin Zhang |
| collection | DOAJ |
| description | Abstract Accumulating evidences reveal that cellular cholesterol deficiency could trigger the onset of Alzheimer’s disease (AD). As a key regulator, 24-dehydrocholesterol reductase (DHCR24) controls cellular cholesterol homeostasis, which was found to be downregulated in AD vulnerable regions and involved in AD-related pathological activities. However, DHCR24 as a potential therapeutic target for AD remains to be identified. In present study, we demonstrated the role of DHCR24 in AD by employing delivery of adeno-associated virus carrying DHCR24 gene into the hippocampus of 5xFAD mice. Here, we found that 5xFAD mice had lower levels of cholesterol and DHCR24 expression, and the cholesterol loss was alleviated by DHCR24 overexpression. Surprisingly, the cognitive impairment of 5xFAD mice was significantly reversed after DHCR24-based gene therapy. Moreover, we revealed that DHCR24 knock-in successfully prevented or reversed AD-related pathology in 5xFAD mice, including amyloid-β deposition, synaptic injuries, autophagy, reactive astrocytosis, microglial phagocytosis and apoptosis. In conclusion, our results firstly demonstrated that the potential value of DHCR24-mediated regulation of cellular cholesterol level as a promising treatment for AD. |
| first_indexed | 2024-03-13T03:18:22Z |
| format | Article |
| id | doaj.art-a03d9475e13d4295803f28f105ca183d |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-13T03:18:22Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-a03d9475e13d4295803f28f105ca183d2023-06-25T11:31:59ZengBMCActa Neuropathologica Communications2051-59602023-06-0111111910.1186/s40478-023-01593-yDHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD miceWen-bin Zhang0Yue Huang1Xiao-rou Guo2Meng-qi Zhang3Xiang-shan Yuan4Heng-bing Zu5Department of Neurology, Jinshan Hospital Affiliated to Fudan UniversityDepartment of Neurology, Jinshan Hospital Affiliated to Fudan UniversityDepartment of Neurology, Jinshan Hospital Affiliated to Fudan UniversityDepartment of Neurology, Jinshan Hospital Affiliated to Fudan UniversityDepartment of Neurology, Jinshan Hospital Affiliated to Fudan UniversityDepartment of Neurology, Jinshan Hospital Affiliated to Fudan UniversityAbstract Accumulating evidences reveal that cellular cholesterol deficiency could trigger the onset of Alzheimer’s disease (AD). As a key regulator, 24-dehydrocholesterol reductase (DHCR24) controls cellular cholesterol homeostasis, which was found to be downregulated in AD vulnerable regions and involved in AD-related pathological activities. However, DHCR24 as a potential therapeutic target for AD remains to be identified. In present study, we demonstrated the role of DHCR24 in AD by employing delivery of adeno-associated virus carrying DHCR24 gene into the hippocampus of 5xFAD mice. Here, we found that 5xFAD mice had lower levels of cholesterol and DHCR24 expression, and the cholesterol loss was alleviated by DHCR24 overexpression. Surprisingly, the cognitive impairment of 5xFAD mice was significantly reversed after DHCR24-based gene therapy. Moreover, we revealed that DHCR24 knock-in successfully prevented or reversed AD-related pathology in 5xFAD mice, including amyloid-β deposition, synaptic injuries, autophagy, reactive astrocytosis, microglial phagocytosis and apoptosis. In conclusion, our results firstly demonstrated that the potential value of DHCR24-mediated regulation of cellular cholesterol level as a promising treatment for AD.https://doi.org/10.1186/s40478-023-01593-yAlzheimer’s disease24-dehydrocholesterol reductase (DHCR24)CholesterolGene therapyNeuroprotectionNeurodegeneration |
| spellingShingle | Wen-bin Zhang Yue Huang Xiao-rou Guo Meng-qi Zhang Xiang-shan Yuan Heng-bing Zu DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice Acta Neuropathologica Communications Alzheimer’s disease 24-dehydrocholesterol reductase (DHCR24) Cholesterol Gene therapy Neuroprotection Neurodegeneration |
| title | DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice |
| title_full | DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice |
| title_fullStr | DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice |
| title_full_unstemmed | DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice |
| title_short | DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice |
| title_sort | dhcr24 reverses alzheimer s disease related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xfad mice |
| topic | Alzheimer’s disease 24-dehydrocholesterol reductase (DHCR24) Cholesterol Gene therapy Neuroprotection Neurodegeneration |
| url | https://doi.org/10.1186/s40478-023-01593-y |
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