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

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 in vivo 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.

• Authors: Minglin Lang, Qiangwang Fan, Lei Wang, Yajun Zheng, Guiran Xiao, Xiaoxi Wang, Wei Wang, Yi Zhong, Bing Zhou
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 34 Issue 11 Pg. 2604-12 (Nov 2013) ISSN: 1558-1497 [Electronic] United States
• PMID: 23827522 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published by Elsevier Inc.

Chemical References

• Amyloid beta-Peptides
• Cation Transport Proteins
• Chelating Agents
• Copper Transporter 1
• Drosophila Proteins
• Peptide Fragments
• Phenanthrolines
• SLC31A1 protein, human
• amyloid beta-protein (1-42)
• bathocuproine sulfonate

Topics

• Age Factors
• Alzheimer Disease (chemically induced, complications, mortality, pathology)
• Amyloid beta-Peptides (toxicity)
• Animals
• Animals, Genetically Modified
• Cation Transport Proteins (genetics, metabolism)
• Cell Count
• Chelating Agents (pharmacology)
• Conditioning, Classical (drug effects, physiology)
• Copper Transporter 1
• Disease Models, Animal
• Drosophila
• Drosophila Proteins (genetics, metabolism)
• Gene Expression Regulation (drug effects, genetics)
• Humans
• Locomotion (drug effects, genetics)
• Longevity (drug effects, genetics)
• Male
• Memory Disorders (chemically induced, genetics)
• Nerve Degeneration (etiology, metabolism)
• Nervous System (metabolism)
• Oxidative Stress (drug effects, genetics)
• Peptide Fragments (toxicity)
• Phenanthrolines (pharmacology)
• RNA Interference (physiology)
• Time Factors