Regulations on the brain iron cycle in the neurodegenerativedisorders

1987年，我们报道了第一例紫纤浆蛋白血症。该疾病揭示了铜蓝蛋白（Cp）在脑铁稳态中的重要作用。我们现在知道：(1)Cp调节铁外排的效率(2)Cp作为铁氧化酶起作用并调节亚铁（Fe2+）氧化为三铁（Fe3+）(3) Cp不直接与转铁蛋白结合(4)Cp稳定细胞表面铁转运蛋白，铁转运蛋白和(5)糖磷酸膦酸苷连接的Cp （GPI-Cp）是大脑中表达的主要形式。在脑内，血清转铁蛋白结合的铁以依赖于转铁蛋白受体1的方式被脑内皮细胞内吞，铁通过铁转运蛋白释放到脑间质液中。细胞外铁被星形胶质细胞足突中发现的GPI -Cp氧化，然后与少突胶质细胞合成的转铁蛋白结合并转运到神经元中。β-淀粉样前体蛋白（APP）与Cp一样具有铁氧化酶活性，并与神经元铁转运蛋白相互作用。大脑需要从血液中获得数倍浓度的铁来维持其正常功能。综上所述，铁代谢分子的已知功能表明，在大脑中存在铁储存和再利用的循环。

In 1987, we described the first case of aceruloplasminemia. This disease revealed an essential role for ceruloplasmin (Cp) in brain iron homeostasis. We now know that(1) Cp regulates the efficiency of iron efflux(2) Cp functions as a ferroxidase and regulates the oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+)(3) Cp does not bind to transferrin directly(4) Cp stabilizes the cell surface iron transporter, ferroportinand (5) glycophosphosinositide-linked Cp (GPI-Cp) is the predominant form expressed in the brain.In the brain, serum transferrin-bound iron is endocytosed by brain endothelial cells in a manner dependent on transferrin receptor 1, and iron is released into the brain interstitial fluid through ferroportin.Extracellular iron is oxidized by GPI -Cp, which is found in the foot processes of astrocytes, and then the iron binds to the transferrin synthesized by oligodendrocytes and is transported into neurons. β-amyloid precursor protein (APP) was found to possess ferroxidase activity like Cp, and to interact with neuron ferroportin. The brain needs several times the concentration of iron obtained from the blood to maintain its normal function. Taken together, the known functions of the iron metabolic molecules suggest the presence of a cycle of iron storage and reutilization within the brain.