Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke
Hemorrhagic stroke, specifically intracerebral hemorrhage (ICH), has been implicated in the development of persistent cognitive impairment, significantly compromising the quality of life for affected individuals. Nevertheless, the precise underlying mechanism remains elusive. Here, we report for the...
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| Language: | English |
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Elsevier
2024-05-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724000624 |
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| author | Xuyang Zhang Huanhuan Li Haomiao Wang Qian Zhang Xueyun Deng Shuixian Zhang Long Wang Chao Guo Fengchun Zhao Yi Yin Tengyuan Zhou Jun Zhong Hui Feng Wei Chen Jun Zhang Hua Feng Rong Hu |
| author_facet | Xuyang Zhang Huanhuan Li Haomiao Wang Qian Zhang Xueyun Deng Shuixian Zhang Long Wang Chao Guo Fengchun Zhao Yi Yin Tengyuan Zhou Jun Zhong Hui Feng Wei Chen Jun Zhang Hua Feng Rong Hu |
| author_sort | Xuyang Zhang |
| collection | DOAJ |
| description | Hemorrhagic stroke, specifically intracerebral hemorrhage (ICH), has been implicated in the development of persistent cognitive impairment, significantly compromising the quality of life for affected individuals. Nevertheless, the precise underlying mechanism remains elusive. Here, we report for the first time that the accumulation of iron within the hippocampus, distal to the site of ICH in the striatum, is causally linked to the observed cognitive impairment with both clinical patient data and animal model. Both susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM) demonstrated significant iron accumulation in the hippocampus of ICH patients, which is far from the actual hematoma. Logistical regression analysis and multiple linear regression analysis identified iron level as an independent risk factor with a negative correlation with post-ICH cognitive impairment. Using a mouse model of ICH, we demonstrated that iron accumulation triggers an excessive activation of neural stem cells (NSCs). This overactivation subsequently leads to the depletion of the NSC pool, diminished neurogenesis, and the onset of progressive cognitive dysfunction. Mechanistically, iron accumulation elevated the levels of reactive oxygen species (ROS), which downregulated the expression of Itga3. Notably, pharmacological chelation of iron accumulation or scavenger of aberrant ROS levels, as well as conditionally overexpressed Itga3 in NSCs, remarkably attenuated the exhaustion of NSC pool, abnormal neurogenesis and cognitive decline in the mouse model of ICH. Together, these results provide molecular insights into ICH-induced cognitive impairment, shedding light on the value of maintaining NSC pool in preventing cognitive dysfunction in patients with hemorrhagic stroke or related conditions. |
| first_indexed | 2024-03-08T00:01:15Z |
| format | Article |
| id | doaj.art-e2319eda454541c88eb3d20c9b1bb5e8 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-24T16:50:04Z |
| publishDate | 2024-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-e2319eda454541c88eb3d20c9b1bb5e82024-03-29T05:50:11ZengElsevierRedox Biology2213-23172024-05-0171103086Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic strokeXuyang Zhang0Huanhuan Li1Haomiao Wang2Qian Zhang3Xueyun Deng4Shuixian Zhang5Long Wang6Chao Guo7Fengchun Zhao8Yi Yin9Tengyuan Zhou10Jun Zhong11Hui Feng12Wei Chen13Jun Zhang14Hua Feng15Rong Hu16Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaClinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, ChinaDepartment of Neurosurgery, The Affiliated Nanchong Central Hospital of North Sichuan Medical College, Nanchong, 637000, China; Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, ChinaDepartment of Neurobiology, College of Basic Medical Sciences, Third Military Medical University (Army Medical University), Chongqing, 400038, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, ChinaDepartment of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), 400038, Chongqing, China; Corresponding author.Hemorrhagic stroke, specifically intracerebral hemorrhage (ICH), has been implicated in the development of persistent cognitive impairment, significantly compromising the quality of life for affected individuals. Nevertheless, the precise underlying mechanism remains elusive. Here, we report for the first time that the accumulation of iron within the hippocampus, distal to the site of ICH in the striatum, is causally linked to the observed cognitive impairment with both clinical patient data and animal model. Both susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM) demonstrated significant iron accumulation in the hippocampus of ICH patients, which is far from the actual hematoma. Logistical regression analysis and multiple linear regression analysis identified iron level as an independent risk factor with a negative correlation with post-ICH cognitive impairment. Using a mouse model of ICH, we demonstrated that iron accumulation triggers an excessive activation of neural stem cells (NSCs). This overactivation subsequently leads to the depletion of the NSC pool, diminished neurogenesis, and the onset of progressive cognitive dysfunction. Mechanistically, iron accumulation elevated the levels of reactive oxygen species (ROS), which downregulated the expression of Itga3. Notably, pharmacological chelation of iron accumulation or scavenger of aberrant ROS levels, as well as conditionally overexpressed Itga3 in NSCs, remarkably attenuated the exhaustion of NSC pool, abnormal neurogenesis and cognitive decline in the mouse model of ICH. Together, these results provide molecular insights into ICH-induced cognitive impairment, shedding light on the value of maintaining NSC pool in preventing cognitive dysfunction in patients with hemorrhagic stroke or related conditions.http://www.sciencedirect.com/science/article/pii/S2213231724000624Hemorrhagic strokeROSNeural stem cell poolNeurogenesisCognitive impairment |
| spellingShingle | Xuyang Zhang Huanhuan Li Haomiao Wang Qian Zhang Xueyun Deng Shuixian Zhang Long Wang Chao Guo Fengchun Zhao Yi Yin Tengyuan Zhou Jun Zhong Hui Feng Wei Chen Jun Zhang Hua Feng Rong Hu Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke Redox Biology Hemorrhagic stroke ROS Neural stem cell pool Neurogenesis Cognitive impairment |
| title | Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke |
| title_full | Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke |
| title_fullStr | Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke |
| title_full_unstemmed | Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke |
| title_short | Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke |
| title_sort | iron ros itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke |
| topic | Hemorrhagic stroke ROS Neural stem cell pool Neurogenesis Cognitive impairment |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724000624 |
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