Iron induces blood-brain barrier alteration contributing to cognitive impairment in β-thalassaemia mice
Abstract Iron overload has been associated with cerebrovascular disease and cognitive impairment in β-thalassaemia patients, typically appearing earlier than in the general population. However, the mechanisms of iron overload on cerebrovascular pathology remain unclear. This study investigated the e...
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Nature Portfolio
2025-01-01
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| author | Parinda Jamrus Nuttanan Pholngam Benjaporn Kiatpakdee Kittikun Viwatpinyo Jim Vadolas Sukonthar Ngampramuan Saovaros Svasti Pornthip Chaichompoo |
| author_facet | Parinda Jamrus Nuttanan Pholngam Benjaporn Kiatpakdee Kittikun Viwatpinyo Jim Vadolas Sukonthar Ngampramuan Saovaros Svasti Pornthip Chaichompoo |
| author_sort | Parinda Jamrus |
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| description | Abstract Iron overload has been associated with cerebrovascular disease and cognitive impairment in β-thalassaemia patients, typically appearing earlier than in the general population. However, the mechanisms of iron overload on cerebrovascular pathology remain unclear. This study investigated the effects of heavy iron overload on the blood-brain barrier and neurohistology, particularly in the CA3 region of hippocampus and its contribution to cognitive impairment in β-thalassaemia mice. Three-month-old female β-thalassaemia and wild-type mice received iron dextran via intraperitoneal injection to induce heavy iron overload. While β-thalassaemia mice with low baseline iron show cognitive impairment at 22 months, equivalent to 70–80 human years, heavy iron overload accelerated cognitive decline, leading to impaired spatial learning and memory by 12 months, equivalent to 35–40 human years, in both β-thalassaemia and wild-type mice. Iron-loaded mice have reduced hippocampal CA3 pyramidal neurons and significant iron accumulation in blood vessels, with no increase in neuronal iron levels. A significant decrease in ZO-1, a tight junction protein, indicated decreased blood-brain barrier integrity and potential iron leakage into the brain. While iron-loading had no effect on astrocytes, elevated Iba1 expression in microglia suggests microglia activation as a protective response. However, persistent iron overload may lead to chronic neuroinflammation, neurodegeneration, and cognitive decline. These results underscore the critical role of iron overload in accelerating cognitive decline in β-thalassaemia and suggest that regular monitoring of iron levels and chelation therapy may help prevent early cognitive impairment, ultimately improving the quality of life for β-thalassaemia patients. |
| format | Article |
| id | doaj-art-5836194732be4020967f7b4652709d23 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-5836194732be4020967f7b4652709d232025-01-05T12:20:21ZengNature PortfolioScientific Reports2045-23222025-01-0115111310.1038/s41598-024-84395-zIron induces blood-brain barrier alteration contributing to cognitive impairment in β-thalassaemia miceParinda Jamrus0Nuttanan Pholngam1Benjaporn Kiatpakdee2Kittikun Viwatpinyo3Jim Vadolas4Sukonthar Ngampramuan5Saovaros Svasti6Pornthip Chaichompoo7Department of Pathobiology, Faculty of Science, Mahidol UniversityThalassemia Research Center, Institute of Molecular Biosciences, Mahidol UniversityThalassemia Research Center, Institute of Molecular Biosciences, Mahidol UniversityResearch Center for Neuroscience, Institute of Molecular Biosciences, Mahidol UniversityCentre for Cancer Research, Hudson Institute of Medical ResearchResearch Center for Neuroscience, Institute of Molecular Biosciences, Mahidol UniversityThalassemia Research Center, Institute of Molecular Biosciences, Mahidol UniversityDepartment of Pathobiology, Faculty of Science, Mahidol UniversityAbstract Iron overload has been associated with cerebrovascular disease and cognitive impairment in β-thalassaemia patients, typically appearing earlier than in the general population. However, the mechanisms of iron overload on cerebrovascular pathology remain unclear. This study investigated the effects of heavy iron overload on the blood-brain barrier and neurohistology, particularly in the CA3 region of hippocampus and its contribution to cognitive impairment in β-thalassaemia mice. Three-month-old female β-thalassaemia and wild-type mice received iron dextran via intraperitoneal injection to induce heavy iron overload. While β-thalassaemia mice with low baseline iron show cognitive impairment at 22 months, equivalent to 70–80 human years, heavy iron overload accelerated cognitive decline, leading to impaired spatial learning and memory by 12 months, equivalent to 35–40 human years, in both β-thalassaemia and wild-type mice. Iron-loaded mice have reduced hippocampal CA3 pyramidal neurons and significant iron accumulation in blood vessels, with no increase in neuronal iron levels. A significant decrease in ZO-1, a tight junction protein, indicated decreased blood-brain barrier integrity and potential iron leakage into the brain. While iron-loading had no effect on astrocytes, elevated Iba1 expression in microglia suggests microglia activation as a protective response. However, persistent iron overload may lead to chronic neuroinflammation, neurodegeneration, and cognitive decline. These results underscore the critical role of iron overload in accelerating cognitive decline in β-thalassaemia and suggest that regular monitoring of iron levels and chelation therapy may help prevent early cognitive impairment, ultimately improving the quality of life for β-thalassaemia patients.https://doi.org/10.1038/s41598-024-84395-zBlood-brain barrierCognitive impairmentBrain pathologyIron overloadβ-Thalassaemia |
| spellingShingle | Parinda Jamrus Nuttanan Pholngam Benjaporn Kiatpakdee Kittikun Viwatpinyo Jim Vadolas Sukonthar Ngampramuan Saovaros Svasti Pornthip Chaichompoo Iron induces blood-brain barrier alteration contributing to cognitive impairment in β-thalassaemia mice Scientific Reports Blood-brain barrier Cognitive impairment Brain pathology Iron overload β-Thalassaemia |
| title | Iron induces blood-brain barrier alteration contributing to cognitive impairment in β-thalassaemia mice |
| title_full | Iron induces blood-brain barrier alteration contributing to cognitive impairment in β-thalassaemia mice |
| title_fullStr | Iron induces blood-brain barrier alteration contributing to cognitive impairment in β-thalassaemia mice |
| title_full_unstemmed | Iron induces blood-brain barrier alteration contributing to cognitive impairment in β-thalassaemia mice |
| title_short | Iron induces blood-brain barrier alteration contributing to cognitive impairment in β-thalassaemia mice |
| title_sort | iron induces blood brain barrier alteration contributing to cognitive impairment in β thalassaemia mice |
| topic | Blood-brain barrier Cognitive impairment Brain pathology Iron overload β-Thalassaemia |
| url | https://doi.org/10.1038/s41598-024-84395-z |
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