Neurobiol Aging 2012 Jan;33 (1): 199.e1-199.e12. [IF:6.634]
Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production.
Wu Z , Du Y , Xue H , Wu Y , Zhou B .
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
清华大学生命科学学院生物膜与膜生物工程国家重点实验室
Abstract
The neurotoxicity of aluminum (Al) - the most abundant metal element on earth - has been known for years. However, the mechanism of Al-induced neurodegeneration and its relationship to Alzheimer's disease are still controversial. In particular, in vivo functional data are lacking. In a Drosophila model with chronic dietary Al overloading, general neurodegeneration and several behavioral changes were observed. Al-induced neurodegeneration is independent of β-amyloid or tau-associated toxicity, suggesting they act in different molecular pathways. Interestingly, Drosophila frataxin (dfh), which causes Friedreich's ataxia if mutated in humans, displayed an interacting effect with Al, suggesting Friedreich's ataxia patients might be more susceptible to Al toxicity. Al-treated flies accumulated large amount of iron and reactive oxygen species (ROS), and exhibited elevated SOD2 activity. Genetic and pharmacological efforts to reduce ROS or chelate excess Fe significantly mitigated Al toxicity. Our results indicate that Al toxicity is mediated through ROS production and iron accumulation and suggest a remedial route to reduce toxicity due to Al exposure.
摘要：
地球上最丰富的金属元素--铝（Al）的神经毒性已被了解多年。但是，铝诱导的神经退行性疾病的机制和其与阿尔茨海默氏病的关系尚有争议。尤其是，在动物活体内的有效数据缺乏。
在慢性铝超载膳食制作的果蝇模型中，观察到了一般的神经退行性病变和一些行为改变。铝诱导的神经退行性疾病与β-淀粉样或牛磺酸相关的毒性是不相关的，这表明他们有不同的分子机制。
有趣的是，果蝇有frataxin（DFH）基因，如果人类的此基因突变，可以导致弗里德共济失调，表明可能与Al相互作用，使弗里德共济失调患者可能更容易受到铝毒影响。
经过铝超载膳食的苍蝇，积累了大量的铁和活性氧（ROS），并且SOD2活性也升高。
遗传学和药理学减少ROS和多余的铁螯合物的努力显著缓解了铝毒性。
我们的研究结果表明，铝毒是由活性氧和铁的积累产生，并提出了减少由于铝暴露产生的铝毒性的治疗途径。
