Division of Environmental Medicine, Department of Chemicals and Radiation, The Norwegian Institute of Public Health, P.O. Box 4404, Nydalen, 0403 Oslo, Norway.
Oxid Med Cell Longev. 2013;2013:726954. doi: 10.1155/2013/726954. Epub 2013 Apr 17.
A dysregulated metal homeostasis is associated with both Alzheimer's (AD) and Parkinson's (PD) diseases; AD patients have decreased cortex and elevated serum copper levels along with extracellular amyloid-beta plaques containing copper, iron, and zinc. For AD, a putative hepcidin-mediated lowering of cortex copper mechanism is suggested. An age-related mild chronic inflammation and/or elevated intracellular iron can trigger hepcidin production followed by its binding to ferroportin which is the only neuronal iron exporter, thereby subjecting it to lysosomal degradation. Subsequently raised neuronal iron levels can induce translation of the ferroportin assisting and copper binding amyloid precursor protein (APP); constitutive APP transmembrane passage lowers the copper pool which is important for many enzymes. Using in silico gene expression analyses, we here show significantly decreased expression of copper-dependent enzymes in AD brain and metallothioneins were upregulated in both diseases. Although few AD exposure risk factors are known, AD-related tauopathies can result from cyanobacterial microcystin and β-methylamino-L-alanine (BMAA) intake. Several environmental exposures may represent risk factors for PD; for this disease neurodegeneration is likely to involve mitochondrial dysfunction, microglial activation, and neuroinflammation. Administration of metal chelators and anti-inflammatory agents could affect disease outcomes.
金属稳态失衡与阿尔茨海默病（AD）和帕金森病（PD）都有关联；AD 患者的皮质减少，血清铜水平升高，同时细胞外淀粉样β斑块含有铜、铁和锌。对于 AD，提出了一种假设的铁调素介导的皮质铜降低机制。与年龄相关的轻度慢性炎症和/或细胞内铁升高可能会触发铁调素的产生，随后铁调素与铁蛋白结合，铁蛋白是唯一的神经元铁输出蛋白，从而使其被溶酶体降解。随后升高的神经元铁水平可诱导铁蛋白辅助和铜结合淀粉样前体蛋白（APP）的翻译；组成型 APP 跨膜转运降低了铜库，铜库对许多酶很重要。通过计算机基因表达分析，我们在这里显示 AD 大脑中铜依赖性酶的表达显著降低，两种疾病中的金属硫蛋白都上调。尽管已知一些 AD 暴露的风险因素，但与 AD 相关的 tau 病可能是由蓝藻微囊藻和β-甲基氨基-L-丙氨酸（BMAA）摄入引起的。一些环境暴露可能是 PD 的风险因素；对于这种疾病，神经退行性变可能涉及线粒体功能障碍、小胶质细胞激活和神经炎症。金属螯合剂和抗炎剂的给药可能会影响疾病的结果。
