Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor
Cholesterol is a major component of the cellular plasma membrane (PM), and its homeostasis is essential for brain health. Dysregulated cholesterol homeostasis has been strongly implicated in the pathogenesis of various neurological disorders, including Alzheimer’s disease (AD). However, in vivo visu...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227525000410 |
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| author | Yi Xu Saixuan Li Yiran Xu Xiaoqin Sun Yuqing Wei Yuejun Wang Shuang Li Yongqi Ji Keyi Hu Yuxia Xu Cuiqing Zhu Bin Lu Dandan Wang |
| author_facet | Yi Xu Saixuan Li Yiran Xu Xiaoqin Sun Yuqing Wei Yuejun Wang Shuang Li Yongqi Ji Keyi Hu Yuxia Xu Cuiqing Zhu Bin Lu Dandan Wang |
| author_sort | Yi Xu |
| collection | DOAJ |
| description | Cholesterol is a major component of the cellular plasma membrane (PM), and its homeostasis is essential for brain health. Dysregulated cholesterol homeostasis has been strongly implicated in the pathogenesis of various neurological disorders, including Alzheimer’s disease (AD). However, in vivo visualization of cholesterol has remained challenging, hindering a comprehensive understanding of AD pathology. In this study, we generated a new sensor combining the split-fluorescent protein tags with YDQA, a derivate of cholesterol-dependent cytolysin PFO. Through a series of validations in cell and C. elegans models, we demonstrate that the new sensor (name as sfPMcho) efficiently detects neuronal PM cholesterol. We further applied this sensor in 5X FAD and APOE KO mice models and revealed the cholesterol changes within neurons. PM cholesterol became sparse and locally aggregated in neuron bodies but significantly accumulated in nerve fibers. Collectively, this study provides a new tool for detecting neuronal PM cholesterol in vivo and uncovers cholesterol abnormalities in AD-related pathology at the cellular level. Further development based on this sensor or a similar strategy is to be expected. |
| format | Article |
| id | doaj-art-efec98d4e8a94107895d00fc9315103c |
| institution | DOAJ |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-efec98d4e8a94107895d00fc9315103c2025-08-20T03:09:03ZengElsevierJournal of Lipid Research0022-22752025-05-0166510078110.1016/j.jlr.2025.100781Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensorYi Xu0Saixuan Li1Yiran Xu2Xiaoqin Sun3Yuqing Wei4Yuejun Wang5Shuang Li6Yongqi Ji7Keyi Hu8Yuxia Xu9Cuiqing Zhu10Bin Lu11Dandan Wang12State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR ChinaState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR ChinaState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR ChinaState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR ChinaState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR ChinaState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR ChinaState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR ChinaState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR ChinaState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR ChinaState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR China; For correspondence: Yuxia Xu; Cuiqing Zhu; Bin Lu; Dandan WangState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR China; For correspondence: Yuxia Xu; Cuiqing Zhu; Bin Lu; Dandan WangDepartment of Endocrinology, Huadong Hospital Affiliated to Fudan University, Shanghai, PR China; For correspondence: Yuxia Xu; Cuiqing Zhu; Bin Lu; Dandan WangState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, PR China; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, PR China; For correspondence: Yuxia Xu; Cuiqing Zhu; Bin Lu; Dandan WangCholesterol is a major component of the cellular plasma membrane (PM), and its homeostasis is essential for brain health. Dysregulated cholesterol homeostasis has been strongly implicated in the pathogenesis of various neurological disorders, including Alzheimer’s disease (AD). However, in vivo visualization of cholesterol has remained challenging, hindering a comprehensive understanding of AD pathology. In this study, we generated a new sensor combining the split-fluorescent protein tags with YDQA, a derivate of cholesterol-dependent cytolysin PFO. Through a series of validations in cell and C. elegans models, we demonstrate that the new sensor (name as sfPMcho) efficiently detects neuronal PM cholesterol. We further applied this sensor in 5X FAD and APOE KO mice models and revealed the cholesterol changes within neurons. PM cholesterol became sparse and locally aggregated in neuron bodies but significantly accumulated in nerve fibers. Collectively, this study provides a new tool for detecting neuronal PM cholesterol in vivo and uncovers cholesterol abnormalities in AD-related pathology at the cellular level. Further development based on this sensor or a similar strategy is to be expected.http://www.sciencedirect.com/science/article/pii/S0022227525000410Alzheimer’s diseasecholesterolplasma membranesensor |
| spellingShingle | Yi Xu Saixuan Li Yiran Xu Xiaoqin Sun Yuqing Wei Yuejun Wang Shuang Li Yongqi Ji Keyi Hu Yuxia Xu Cuiqing Zhu Bin Lu Dandan Wang Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor Journal of Lipid Research Alzheimer’s disease cholesterol plasma membrane sensor |
| title | Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor |
| title_full | Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor |
| title_fullStr | Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor |
| title_full_unstemmed | Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor |
| title_short | Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor |
| title_sort | visualize neuronal membrane cholesterol with split fluorescent protein tagged ydqa sensor |
| topic | Alzheimer’s disease cholesterol plasma membrane sensor |
| url | http://www.sciencedirect.com/science/article/pii/S0022227525000410 |
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