Laboratory of Applied Immunology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Zip Code 86.038-440 Brazil; Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Zip Code 86.038-440 Brazil.
Laboratory of Applied Immunology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Zip Code 86.038-440 Brazil.
Neurotoxicology. 2019 Sep;74:230-241. doi: 10.1016/j.neuro.2019.07.007. Epub 2019 Aug 1.
Metals are involved in different pathophysiological mechanisms associated with neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS). The aim of this study was to review the effects of the essential metals zinc (Zn), copper (Cu), manganese (Mn) and iron (Fe) on the central nervous system (CNS), as well as the mechanisms involved in their neurotoxicity. Low levels of Zn as well as high levels of Cu, Mn, and Fe participate in the activation of signaling pathways of the inflammatory, oxidative and nitrosative stress (IO&NS) response, including nuclear factor kappa B and activator protein-1. The imbalance of these metals impairs the structural, regulatory, and catalytic functions of different enzymes, proteins, receptors, and transporters. Neurodegeneration occurs via association of metals with proteins and subsequent induction of aggregate formation creating a vicious cycle by disrupting mitochondrial function, which depletes adenosine triphosphate and induces IO&NS, cell death by apoptotic and/or necrotic mechanisms. In AD, at low levels, Zn suppresses β-amyloid-induced neurotoxicity by selectively precipitating aggregation intermediates; however, at high levels, the binding of Zn to β-amyloid may enhance formation of fibrillar β-amyloid aggregation, leading to neurodegeneration. High levels of Cu, Mn and Fe participate in the formation α-synuclein aggregates in intracellular inclusions, called Lewy Body, that result in synaptic dysfunction and interruption of axonal transport. In PD, there is focal accumulation of Fe in the substantia nigra, while in AD a diffuse accumulation of Fe occurs in various regions, such as cortex and hippocampus, with Fe marginally increased in the senile plaques. Zn deficiency induces an imbalance between T helper (Th)1 and Th2 cell functions and a failure of Th17 down-regulation, contributing to the pathogenesis of MS. In MS, elevated levels of Fe occur in certain brain regions, such as thalamus and striatum, which may be due to inflammatory processes disrupting the blood-brain barrier and attracting Fe-rich macrophages. Delineating the specific mechanisms by which metals alter redox homeostasis is essential to understand the pathophysiology of AD, PD, and MS and may provide possible new targets for their prevention and treatment of the patients affected by these NDDs.
金属参与与神经退行性疾病（NDDs）相关的不同病理生理机制，包括阿尔茨海默病（AD）、帕金森病（PD）和多发性硬化症（MS）。本研究旨在综述必需金属锌（Zn）、铜（Cu）、锰（Mn）和铁（Fe）对中枢神经系统（CNS）的影响，以及它们神经毒性涉及的机制。Zn 水平低以及 Cu、Mn 和 Fe 水平高，参与了炎症、氧化和硝化应激（IO&NS）反应的信号通路的激活，包括核因子 kappa B 和激活蛋白-1。这些金属的失衡会损害不同酶、蛋白质、受体和转运体的结构、调节和催化功能。神经退行性变通过金属与蛋白质的结合以及随后诱导聚集体形成而发生，通过破坏线粒体功能产生恶性循环，耗尽三磷酸腺苷并诱导 IO&NS，通过凋亡和/或坏死机制导致细胞死亡。在 AD 中，Zn 水平低时通过选择性沉淀聚集中间产物抑制β-淀粉样蛋白诱导的神经毒性；然而，Zn 水平高时，Zn 与β-淀粉样蛋白的结合可能增强纤维状β-淀粉样蛋白聚集的形成，导致神经退行性变。高水平的 Cu、Mn 和 Fe 参与细胞内包涵体中α-突触核蛋白聚集体的形成，称为路易体，导致突触功能障碍和轴突运输中断。在 PD 中，黑质中存在 Fe 的局灶性积累，而在 AD 中，皮质和海马等不同区域中存在 Fe 的弥漫性积累，在老年斑中 Fe 略有增加。Zn 缺乏导致辅助性 T（Th）1 和 Th2 细胞功能失衡和 Th17 下调失败，导致 MS 的发病机制。在 MS 中，某些脑区如丘脑和纹状体中出现 Fe 水平升高，这可能是由于炎症过程破坏血脑屏障并吸引富含 Fe 的巨噬细胞所致。阐明金属改变氧化还原平衡的具体机制对于理解 AD、PD 和 MS 的病理生理学至关重要，并可能为这些 NDDs 患者的预防和治疗提供新的可能靶点。
