Jamrus Parinda, Pholngam Nuttanan, Kiatpakdee Benjaporn, Viwatpinyo Kittikun, Vadolas Jim, Ngampramuan Sukonthar, Svasti Saovaros, Chaichompoo Pornthip
Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand.
Sci Rep. 2025 Jan 2;15(1):533. doi: 10.1038/s41598-024-84395-z.
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.
铁过载与β地中海贫血患者的脑血管疾病和认知障碍有关，通常比普通人群出现得更早。然而，铁过载对脑血管病理的作用机制仍不清楚。本研究调查了重度铁过载对血脑屏障和神经组织学的影响，特别是在海马体CA3区域，以及其对β地中海贫血小鼠认知障碍的影响。对3个月大的雌性β地中海贫血小鼠和野生型小鼠进行腹腔注射右旋糖酐铁以诱导重度铁过载。虽然基线铁含量低的β地中海贫血小鼠在22个月时出现认知障碍，相当于人类70 - 80岁，但重度铁过载加速了认知衰退，导致β地中海贫血小鼠和野生型小鼠在12个月时空间学习和记忆受损，相当于人类35 - 40岁。铁负荷小鼠海马体CA3区锥体神经元减少，血管中有大量铁蓄积，神经元铁水平无升高。紧密连接蛋白ZO - 1显著减少，表明血脑屏障完整性降低，可能有铁泄漏入脑。虽然铁负荷对星形胶质细胞没有影响，但小胶质细胞中Iba1表达升高表明小胶质细胞被激活作为一种保护反应。然而，持续的铁过载可能导致慢性神经炎症、神经退行性变和认知衰退。这些结果强调了铁过载在加速β地中海贫血患者认知衰退中的关键作用，并表明定期监测铁水平和螯合治疗可能有助于预防早期认知障碍，最终改善β地中海贫血患者的生活质量。
