Hao Qiang, Maret Wolfgang
Department of Preventive Medicine & Community Health, University of Texas Medical Branch, Galveston, TX 77555, USA.
J Alzheimers Dis. 2005 Nov;8(2):161-70; discussion 209-15. doi: 10.3233/jad-2005-8209.
Alzheimer's disease is associated with oxidative stress and changes in metal metabolism. Among the essential trace metals, zinc has the greatest number and variety of functions in hundreds of enzymes and thousands of protein domains with different types of zinc finger motifs. Moreover, zinc ions are stored in synaptic vesicles of specialized neurons and released during neuronal activity. Based on this multitude of functions, one would expect that impairment of zinc homeostasis in the brain has far-reaching consequences. In spite of the fact that zinc ions are redox-inert in biology, they have profound effects on redox metabolism. Thus, both zinc deficiency and zinc overload elicit oxidative stress that can lead to the death of nerve cells. These pro-oxidant functions contrast with pro-antioxidant functions in a range of physiological zinc concentrations. Oxidative or nitrosative stress can release zinc from proteins with zinc finger and cluster motifs and re-distribute zinc, thereby changing the functions of the proteins from which it is released and to which it binds. The transduction of redox signals into zinc signals and vice versa affects mitochondrial functions and signaling pathways (NF-kappaB, p53, AP-1) where zinc and the zinc donor/acceptor pair metallothionein/thionein are critically involved in life and death decisions of the cell.
阿尔茨海默病与氧化应激及金属代谢变化有关。在必需的微量金属中，锌在数百种酶和数千个具有不同类型锌指基序的蛋白质结构域中具有最多样化的功能。此外，锌离子储存在特殊神经元的突触小泡中，并在神经元活动期间释放。基于这些众多的功能，可以预期大脑中锌稳态的损害会产生深远的后果。尽管锌离子在生物学中是氧化还原惰性的，但它们对氧化还原代谢有深远影响。因此，锌缺乏和锌过载都会引发氧化应激，进而导致神经细胞死亡。在一系列生理锌浓度下，这些促氧化功能与抗氧化功能形成对比。氧化或亚硝化应激可使锌从具有锌指和簇基序的蛋白质中释放出来，并重新分布锌，从而改变其释放来源及结合对象的蛋白质功能。氧化还原信号与锌信号之间的转换，反之亦然，会影响线粒体功能和信号通路（核因子κB、p53、激活蛋白1），其中锌以及锌供体/受体对金属硫蛋白/硫蛋白在细胞的生死决策中起着关键作用。
