Yokel Robert A
College of Pharmacy and Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington, KY 40536-0082, USA.
J Alzheimers Dis. 2006 Nov;10(2-3):223-53. doi: 10.3233/jad-2006-102-309.
The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc;{-} and an organic anion transporter, and results suggesting transporter-mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and Wilson's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of all processes that contribute to brain metal concentrations.
许多神经退行性疾病的病因仅部分归因于后天特征，这表明环境因素可能也有影响。金属稳态失衡会引发或被认为与许多神经退行性疾病有关。本文综述了金属通过血脑屏障（大脑摄取金属的主要途径）、脉络丛以及从鼻腔的感觉神经摄取的过程。列出了在血脑屏障处已被描述的转运体，以说明物质进出大脑的广泛可能性。综述了铝在阿尔茨海默病中的争议性作用、转铁蛋白受体介导的内吞作用使大脑摄取铝的证据以及系统Xc⁻和一种有机阴离子转运体摄取柠檬酸铝的证据，还有转运体介导铝从大脑流出的相关结果。讨论了锰产生帕金森综合征样症状的能力、转铁蛋白依赖性和非转铁蛋白依赖性机制摄取锰的证据（其中可能包括储存性钙通道）以及缺乏转运体介导的锰从大脑流出的情况。介绍了大脑摄取铁的转铁蛋白依赖性和非依赖性机制的证据。总结了铜转运体ATP7A和ATP7B及其在门克斯病和威尔逊病中的作用。L - 组氨酸和D - 组氨酸促进大脑对锌的摄取，但尚未确定是否存在转运体参与。大脑对铅的摄取可能涉及非能量依赖性过程、储存性钙通道和/或ATP依赖性钙泵。甲基汞可与L - 半胱氨酸形成类似蛋氨酸的复合物，从而通过L系统进行转运。讨论了锌转运体ZnT和Zip在调节大脑锌含量方面的假定作用。尽管已经确定了一些金属的大脑摄取机制，但大脑中金属的流出很少受到关注，这妨碍了对所有影响大脑金属浓度过程的整合。
