| RRC ID |
28067
|
| Author |
Lang M, Fan Q, Wang L, Zheng Y, Xiao G, Wang X, Wang W, Zhong Y, Zhou B.
|
| Title |
Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates Aβ42-induced Alzheimer's disease-like symptoms.
|
| Journal |
Neurobiol Aging
|
| 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.
|
| Volume |
34(11)
|
| Pages |
2604-12
|
| Published |
2013-11-1
|
| DOI |
10.1016/j.neurobiolaging.2013.05.029
|
| PII |
S0197-4580(13)00242-X
|
| PMID |
23827522
|
| PMC |
PMC3770863
|
| MeSH |
Age Factors
Alzheimer Disease / chemically induced*
Alzheimer Disease / complications
Alzheimer Disease / mortality
Alzheimer Disease / pathology*
Amyloid beta-Peptides / toxicity*
Animals
Animals, Genetically Modified
Cation Transport Proteins / genetics
Cation Transport Proteins / metabolism*
Cell Count
Chelating Agents / pharmacology
Conditioning, Classical / drug effects
Conditioning, Classical / physiology
Copper Transporter 1
Disease Models, Animal
Drosophila
Drosophila Proteins / genetics
Drosophila Proteins / metabolism
Gene Expression Regulation / drug effects
Gene Expression Regulation / genetics
Humans
Locomotion / drug effects
Locomotion / genetics
Longevity / drug effects*
Longevity / genetics
Male
Memory Disorders / chemically induced
Memory Disorders / genetics
Nerve Degeneration / etiology
Nerve Degeneration / metabolism
Nervous System / metabolism*
Oxidative Stress / drug effects
Oxidative Stress / genetics
Peptide Fragments / toxicity*
Phenanthrolines / pharmacology
RNA Interference / physiology
Time Factors
|
| IF |
4.347
|
| Times Cited |
24
|
|
WOS Category
|
GERIATRICS & GERONTOLOGY
NEUROSCIENCES
|
| Resource |
| Drosophila |
7459R-2 |
