Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates Aβ42-induced Alzheimer's disease-like symptoms

NEUROBIOLOGY OF AGING

卷:34

Article

Lang, Minglin^1,2,4  Fan, Qiangwang¹  Wang, Lei^1,3  Zheng, Yajun²  Xiao, Guiran¹  Wang, Xiaoxi¹  Wang, Wei⁵  Zhong, Yi^1,3  Zhou, Bing¹ 

[1] Tsinghua Univ, State Key Lab Biomembrane & Membrane Biotechnol, Sch Life Sci, Beijing 100084, Peoples R China

[2] Agr Univ Hebei, Coll Life Sci, Baoding, Peoples R China

[3] Beijing Univ Chem Technol, Coll Life Sci & Technol, Beijing 100029, Peoples R China

[4] Kansas State Univ, Dept Biochem & Mol Biophys, Manhattan, KS 66502 USA

[5] Edith Cowan Univ, Sch Med Sci, Perth, WA, Australia

关键词: Alzheimer's disease;    Drosophila;    Copper;    Amyloid-beta;    Neurodegeneration;    High-affinity copper importer;    Ctr1;    DmATP7;   

DOI  :  10.1016/j.neurobiolaging.2013.05.029

来源: Elsevier

【 摘 要 】

Disruption of copper homeostasis has been implicated in Alzheimer's disease (AD) during the last 2 decades; however, whether copper is a friend or a foe is controversial. Within a genetically tractable Drosophila AD model, we manipulated the expression of human high-affinity copper importer orthologous in Drosophila to explore the in vivo roles of copper ions in the development of AD. We found that inhibition of Ctr1C expression by RNAi in A beta-expressing flies significantly reduced copper accumulation in the brains of the flies as well as ameliorating neurodegeneration, enhancing climbing ability, and prolonging lifespan. Interestingly, Ctr1C inhibition led to a significant increase in higher-molecular-weight A beta 42 forms in brain lysates, whereas it was accompanied by a trend of decreased expression of amyloid-beta degradation proteases (including NEP1-3 and IDE) with age and reduced Cu-A beta interaction-induced oxidative stress in Ctr1C RNAi flies. Similar results were obtained from inhibiting another copper importer Ctr1B and overexpressing a copper exporter DmATP7 in the nervous system of AD flies. These results imply that copper may play a causative role in developing AD, as either A beta oligomers or aggregates were less toxic in a reduced copper environment or one with less copper binding. Early manipulation of brain copper uptake can have a great effect on A beta pathology. Published by Elsevier Inc.

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