Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production.
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.
Wu
Zhihao
Z
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Du
Yumei
Y
Xue
Hua
H
Wu
Yongsheng
Y
Zhou
Bing
B
D000535:Aluminum / Q000633:toxicity*; D000544:Alzheimer Disease / Q000139:chemically induced* / Q000378:metabolism; D000818:Animals; D004331:Drosophila melanogaster; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D000096923:Frataxin; D000099156:Superoxide Dismutase 2
D000535:Aluminum; D007501:Iron; D033862:Iron-Binding Proteins; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000096923:Frataxin; D000099156:Superoxide Dismutase 2