Institute of Translational & Precision Medicine, Nantong University, Nantong, 226019, China.
Laboratory of Neuropharmacology, School of Pharmacy, & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 201203, China.
Biol Rev Camb Philos Soc. 2019 Oct;94(5):1672-1684. doi: 10.1111/brv.12521. Epub 2019 Jun 12.
Brain iron is a crucial participant and regulator of normal physiological activity. However, excess iron is involved in the formation of free radicals, and has been associated with oxidative damage to neuronal and other brain cells. Abnormally high brain iron levels have been observed in various neurodegenerative diseases, including neurodegeneration with brain iron accumulation, Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the key question of why iron levels increase in the relevant regions of the brain remains to be answered. A full understanding of the homeostatic mechanisms involved in brain iron transport and metabolism is therefore critical not only for elucidating the pathophysiological mechanisms responsible for excess iron accumulation in the brain but also for developing pharmacological interventions to disrupt the chain of pathological events occurring in these neurodegenerative diseases. Numerous studies have been conducted, but to date no effort to synthesize these studies and ideas into a systematic and coherent summary has been made, especially concerning iron transport across the luminal (apical) membrane of the capillary endothelium and the membranes of different brain cell types. Herein, we review key findings on brain iron transport, highlighting the mechanisms involved in iron transport across the luminal (apical) as well as the abluminal (basal) membrane of the blood-brain barrier, the blood-cerebrospinal fluid barrier, and iron uptake and release in neurons, oligodendrocytes, astrocytes and microglia within the brain. We offer suggestions for addressing the many important gaps in our understanding of this important topic, and provide new insights into the potential causes of abnormally increased iron levels in regions of the brain in neurodegenerative disorders.
脑铁是正常生理活动的关键参与者和调节者。然而，过量的铁会参与自由基的形成，并与神经元和其他脑细胞的氧化损伤有关。在各种神经退行性疾病中，包括伴有脑铁蓄积的神经退行性变、阿尔茨海默病、帕金森病和亨廷顿病，都观察到异常高的脑铁水平。然而，为什么铁水平在大脑的相关区域增加的关键问题仍有待回答。因此，充分了解脑铁运输和代谢的稳态机制不仅对于阐明导致脑内铁过量积累的病理生理机制至关重要，而且对于开发药理学干预措施以破坏这些神经退行性疾病中发生的病理事件链也至关重要。已经进行了许多研究，但迄今为止，还没有人努力将这些研究和想法综合成一个系统和连贯的总结，特别是关于铁在毛细血管内皮细胞的腔（顶）膜和不同脑细胞类型的膜中的运输。在此，我们回顾了脑铁运输的关键发现，强调了铁在血脑屏障的腔（顶）膜以及血脑脊液屏障中的运输机制，以及神经元、少突胶质细胞、星形胶质细胞和小胶质细胞中铁的摄取和释放。我们提出了一些建议，以解决我们对这一重要主题理解中的许多重要差距，并为神经退行性疾病中脑内区域铁水平异常升高的潜在原因提供新的见解。
