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

Document Type

Journal Article

Keywords

Alzheimer's disease, Amyloid-β, Copper, Ctr1, DmATP7, Drosophila, High-affinity copper importer, Neurodegenerationamyloid beta protein, brain protein, cation transport protein, copper ion, Ctr1 protein, Ctr1B protein, Ctr1C protein, DmATP7 protein, IDE protein, isoprotein, NEP1 protein, NEP2 protein, NEP3 protein, proteinase, unclassified drug, Alzheimer disease, animal experiment, animal tissue, article, bioaccumulation, brain metabolism, cation transport, climbing, controlled study, copper brain accumulation, copper metabolism, Ctr1C gene, disease association, disease model, Drosophila, gene, life extension, molecular weight, motor performance, nerve degeneration, nonhuman, oxidative stress, priority journal, protein degradation, protein expression, protein interaction, protein structure, RNA interference, sequence homology, Alzheimer's disease, Amyloid-β, Copper, Ctr1, DmATP7, Drosophila, High-affinity copper importer, Neurodegeneration, Age Factors, Alzheimer Disease, Amyloid beta-Peptides, Animals, Animals, Genetically Modified, Cation Transport Proteins, Cell Count, Chelating Agents, Conditioning, Classical, Disease Models, Animal, Drosophila, Drosophila Proteins, Gene Expression Regulation, Humans, Locomotion, Longevity, Male, Memory Disorders, Nerve Degeneration, Nervous System, Oxidative Stress, Peptide Fragments, Phenanthrolines, RNA Interference, Time Factors

Publisher

Elsevier

Faculty

Faculty of Health, Engineering and Science

School

School of Medical Sciences / Systems and Intervention Research Centre for Health

RAS ID

15908

Comments

Lang, M., Fan, Q., Wang, L., Zheng, Y., Xiao, G., Wang, X., Wang, W. , Zhong, Y., & Zhou, B. (2013). 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, 34(11), 2604-2612. Available here

Abstract

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 invivo roles of copper ions in the development of AD. We found that inhibition of Ctr1C expression by RNAi in Aβ-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 Aβ42 forms in brain lysates, whereas it was accompanied by a trend of decreased expression of amyloid-β degradation proteases (including NEP1-3 and IDE) with age and reduced Cu-Aβ 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 Aβ 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 Aβ pathology.

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Link to publisher version (DOI)

10.1016/j.neurobiolaging.2013.05.029