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 two 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, while 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.

Biological metals and metal-targeting compounds in major neurodegenerative diseases

“…Support for the pathogenic relevance of Ab:Cu assemblies has also come from studies of transgenic drosophila, where copper chelation or suppression of Ctr1C (a copper importer), rescues the toxic phenotype. 209 Similar results were achieved by inhibiting another copper importer, Ctr1B, and by overexpressing a copper exporter DmATP7 in the nervous system of the Ab transgenic flies. 209 The ability of Ab to coordinate and trap Cu in an extracellular environment suggests this may result in a deficiency of Cu in the cytoplasm of neurons resulting in certain cellular functions being inhibited.…”

“…345 Confirming a role for copper interaction with mutant huntingtin in promoting disease pathogenesis, lowering central nervous system copper levels with either Ctr1B suppression or DmATP7A overexpression rescued lethality and neuropathology in two polyQ transgenic Drosophila models of HD. 209 The Cu + chelator bathocuproine disulfonate and Cu 2+ chelator, clioquinol, significantly rescued the survival rate of the Htt transgenic flies, whereas supplementation of additional CuCl 2 worsened the survival defect. 209 Ablation of the Cu 2+ coordination sites on mutant Htt 279 generated a form of the protein that, even when overexpressed, had markedly less toxicity than the parental mutant in a transgenic Drosophila.…”

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

“…The proposal for direct chelation therapy of Cu ions to work in this disorder is still in discussion [ 265 ]. Support for the lowering cellular Cu levels comes from the Drosophila model of AD, where although copper chelation or genetic knockdown of copper transporters (Ctr1C) decreased the expression of Aβ degrading proteases but rescued the toxic phenotype [ 336 ]. Similar results were also observed by silencing the expression of Ctr1B, or when copper exporter DmATP7 [ 336 ] and dMTF-1 or MtnA [ 94 ] were overexpressed in the nervous system of the Aβ transgenic flies.…”

Alzheimer’s disease due to loss of function: A new synthesis of the available data

“…iii) Inhibition of copper transporters increase Aβ in brain lysates and decrease expression of Aβ-degrading proteases [292]. iv) Copper-induced toxicity in rabbits leads to learning impairment and to enhanced Aβ plaque formation, suggesting that production of Aβ from APP increases with metal status [293].…”