Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, No. 20, Nan Er Huan East Road, Shijiazhuang, 050024, China.
Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, No. 20, Nan Er Huan East Road, Shijiazhuang, 050024, China.
Free Radic Biol Med. 2020 Oct;158:84-95. doi: 10.1016/j.freeradbiomed.2020.07.012. Epub 2020 Jul 21.
Iron overload in the brain and iron-induced oxidative damage have been considered to play key roles in the pathogenesis of Alzheimer's disease (AD). Hepcidin is a peptide that regulates systemic iron metabolism by interacting with iron exporter ferroportin 1 (FPN1). Studies have indicated that the astrocyte hepcidin could regulate brain iron intake at the blood-brain barrier and injection of hepcidin into brain attenuated iron deposition in the brain. However, whether overexpression of hepcidin in astrocytes of APP/PS1 transgenic mice can alleviate AD symptoms by reducing iron deposition has not been evaluated. In this study, we overexpressed hepcidin in astrocytes of APP/PS1 mice and investigated its effects on β-amyloid (Aβ) aggregation, neuronal loss, iron deposition and iron-induced oxidative damages. Our results showed that the elevated expression of astrocyte hepcidin in APP/PS1 mice significantly improved their cognitive decline, and partially alleviated the formation of Aβ plaques in cortex and hippocampus. Further investigations revealed that overexpression of hepcidin in astrocytes significantly reduced iron levels in cortex and hippocampus of APP/PS1 mice, especially iron content in neurons, which led to the reduction of iron accumulation-induced oxidative stress and neuroinflammation, and finally decreased neuronal cell death in the cortex and hippocampus of APP/PS1 mice. This study demonstrated that overexpression of hepcidin in astrocytes of APP/PS1 mice could partially alleviate AD symptoms and delay the pathological process of AD.
脑铁过载和铁诱导的氧化损伤被认为在阿尔茨海默病（AD）的发病机制中起关键作用。铁调素是一种通过与铁输出蛋白 Ferroportin 1（FPN1）相互作用来调节全身铁代谢的肽。研究表明，星形胶质细胞铁调素可以在血脑屏障调节脑铁摄取，并且向脑内注射铁调素可以减轻脑内铁沉积。然而，星形胶质细胞中铁调素的过表达是否可以通过减少铁沉积来减轻 APP/PS1 转基因小鼠的 AD 症状尚未得到评估。在本研究中，我们在 APP/PS1 小鼠的星形胶质细胞中过表达铁调素，研究其对β-淀粉样蛋白（Aβ）聚集、神经元丢失、铁沉积和铁诱导的氧化损伤的影响。我们的结果表明，APP/PS1 小鼠星形胶质细胞中铁调素的表达升高显著改善了其认知能力下降，并部分缓解了皮质和海马区 Aβ斑块的形成。进一步的研究表明，星形胶质细胞中铁调素的过表达显著降低了 APP/PS1 小鼠皮质和海马区的铁水平，尤其是神经元中的铁含量，这导致了铁积累诱导的氧化应激和神经炎症的减少，最终减少了 APP/PS1 小鼠皮质和海马区的神经元细胞死亡。这项研究表明，在 APP/PS1 小鼠的星形胶质细胞中过表达铁调素可以部分缓解 AD 症状并延缓 AD 的病理过程。
