Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice
Introduction: Nav1.6 is closely related to the pathology of Alzheimer’s Disease (AD), and astrocytes have recently been identified as a significant source of β-amyloid (Aβ). However, little is known about the connection between Nav1.6 and astrocyte-derived Aβ. Objective: This study explored the cruc...
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2025-06-01
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| author | Xin Wang Wei Wu Guang Yang Xue-Wei Yang Xu Ma Dan-Dan Zhu Kabir Ahmad Khizar Khan Ying-Zi Wang Ao-Ran Sui Song-Yu Guo Yue Kong Bo Yuan Tian-Yuan Luo Cheng-Kang Liu Peng Zhang Yue Zhang Qi-Fa Li Bin Wang Qiong Wu Xue-Fei Wu Zhi-Cheng Xiao Quan-Hong Ma Shao Li |
| author_facet | Xin Wang Wei Wu Guang Yang Xue-Wei Yang Xu Ma Dan-Dan Zhu Kabir Ahmad Khizar Khan Ying-Zi Wang Ao-Ran Sui Song-Yu Guo Yue Kong Bo Yuan Tian-Yuan Luo Cheng-Kang Liu Peng Zhang Yue Zhang Qi-Fa Li Bin Wang Qiong Wu Xue-Fei Wu Zhi-Cheng Xiao Quan-Hong Ma Shao Li |
| author_sort | Xin Wang |
| collection | DOAJ |
| description | Introduction: Nav1.6 is closely related to the pathology of Alzheimer’s Disease (AD), and astrocytes have recently been identified as a significant source of β-amyloid (Aβ). However, little is known about the connection between Nav1.6 and astrocyte-derived Aβ. Objective: This study explored the crucial role of Nav1.6 in mediated astrocyte-derived Aβ in AD and knockdown astrocytic Nav1.6 alleviates AD progression by promoting autophagy and lysosome-APP fusion. Methods: A mouse model for astrocytic Nav1.6 knockdown was constructed to study the effects of astrocytic Nav1.6 on amyloidosis. The role of astrocytic Nav1.6 on autophagy and lysosome-APP(amyloid precursor protein) fusion was used by transmission electron microscope, immunostaining, western blot and patch clamp. Glial cell activation was detected using immunostaining. Neuroplasticity and neural network were assessed using patch-clamp, Golgi stain and EEG recording. Behavioral experiments were performed to evaluate cognitive defects. Results: Astrocytic Nav1.6 knockdown reduces amyloidosis, alleviates glial cell activation and morphological complexity, improves neuroplasticity and abnormal neural networks, as well as promotes learning and memory abilities in APP/PS1 mice. Astrocytic Nav1.6 knockdown reduces itself-derived Aβ by promoting lysosome- APP fusion, which is related to attenuating reverse Na+-Ca2+ exchange current thus reducing intracellular Ca2+ to facilitate autophagic through AKT/mTOR/ULK pathway. Conclusion: Our findings unveil the crucial role of astrocyte-specific Nav1.6 in reducing astrocyte-derived Aβ, highlighting its potential as a cell-specific target for modulating AD progression. |
| format | Article |
| id | doaj-art-bc3d4ce4b7984d3fad2243340d07c3e5 |
| institution | Kabale University |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
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| series | Journal of Advanced Research |
| spelling | doaj-art-bc3d4ce4b7984d3fad2243340d07c3e52025-08-20T03:47:41ZengElsevierJournal of Advanced Research2090-12322025-06-017245146610.1016/j.jare.2024.07.024Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like miceXin Wang0Wei Wu1Guang Yang2Xue-Wei Yang3Xu Ma4Dan-Dan Zhu5Kabir Ahmad6Khizar Khan7Ying-Zi Wang8Ao-Ran Sui9Song-Yu Guo10Yue Kong11Bo Yuan12Tian-Yuan Luo13Cheng-Kang Liu14Peng Zhang15Yue Zhang16Qi-Fa Li17Bin Wang18Qiong Wu19Xue-Fei Wu20Zhi-Cheng Xiao21Quan-Hong Ma22Shao Li23Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDepartment of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, ChinaDevelopment and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, AustraliaInstitute of Neuroscience & Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou 215123, China; Department of Neurology and Clinical Research Center of Neurological Disease, the second affilitated Hospital of Soochow University, Suzhou, Jiangsu 215021, China; Corresponding authors.Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, Liaoning 116044, China; Corresponding authors.Introduction: Nav1.6 is closely related to the pathology of Alzheimer’s Disease (AD), and astrocytes have recently been identified as a significant source of β-amyloid (Aβ). However, little is known about the connection between Nav1.6 and astrocyte-derived Aβ. Objective: This study explored the crucial role of Nav1.6 in mediated astrocyte-derived Aβ in AD and knockdown astrocytic Nav1.6 alleviates AD progression by promoting autophagy and lysosome-APP fusion. Methods: A mouse model for astrocytic Nav1.6 knockdown was constructed to study the effects of astrocytic Nav1.6 on amyloidosis. The role of astrocytic Nav1.6 on autophagy and lysosome-APP(amyloid precursor protein) fusion was used by transmission electron microscope, immunostaining, western blot and patch clamp. Glial cell activation was detected using immunostaining. Neuroplasticity and neural network were assessed using patch-clamp, Golgi stain and EEG recording. Behavioral experiments were performed to evaluate cognitive defects. Results: Astrocytic Nav1.6 knockdown reduces amyloidosis, alleviates glial cell activation and morphological complexity, improves neuroplasticity and abnormal neural networks, as well as promotes learning and memory abilities in APP/PS1 mice. Astrocytic Nav1.6 knockdown reduces itself-derived Aβ by promoting lysosome- APP fusion, which is related to attenuating reverse Na+-Ca2+ exchange current thus reducing intracellular Ca2+ to facilitate autophagic through AKT/mTOR/ULK pathway. Conclusion: Our findings unveil the crucial role of astrocyte-specific Nav1.6 in reducing astrocyte-derived Aβ, highlighting its potential as a cell-specific target for modulating AD progression.http://www.sciencedirect.com/science/article/pii/S2090123224003096Alzheimer’s diseaseSodium channels Nav1.6Astrocytesβ-amyloidAmyloid precursor proteinAutophagy-lysosome pathway |
| spellingShingle | Xin Wang Wei Wu Guang Yang Xue-Wei Yang Xu Ma Dan-Dan Zhu Kabir Ahmad Khizar Khan Ying-Zi Wang Ao-Ran Sui Song-Yu Guo Yue Kong Bo Yuan Tian-Yuan Luo Cheng-Kang Liu Peng Zhang Yue Zhang Qi-Fa Li Bin Wang Qiong Wu Xue-Fei Wu Zhi-Cheng Xiao Quan-Hong Ma Shao Li Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice Journal of Advanced Research Alzheimer’s disease Sodium channels Nav1.6 Astrocytes β-amyloid Amyloid precursor protein Autophagy-lysosome pathway |
| title | Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice |
| title_full | Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice |
| title_fullStr | Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice |
| title_full_unstemmed | Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice |
| title_short | Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice |
| title_sort | cell specific nav1 6 knockdown reduced astrocyte derived aβ by reverse na ca2 transporter mediated autophagy in alzheimer like mice |
| topic | Alzheimer’s disease Sodium channels Nav1.6 Astrocytes β-amyloid Amyloid precursor protein Autophagy-lysosome pathway |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224003096 |
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