Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates Aβ42-induced Alzheimer's disease-like symptoms.
Inhibition of human high-affinity copper importer Ctr1 orthologous in the nervous system of Drosophila ameliorates Aβ42-induced Alzheimer's disease-like symptoms.
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DOI：
10.1016/j.neurobiolaging.2013.05.029
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发表时间：
2013-11
影响因子：
4.2
通讯作者：
Zhou B
中科院分区：
文献类型：
--
作者：
Lang M;Fan Q;Wang L;Zheng Y;Xiao G;Wang X;Wang W;Zhong Y;Zhou B
在过去的二十年中，铜稳态的破坏与阿尔茨海默病（AD）有关;然而，铜是朋友还是敌人是有争议的。在一个遗传学上易处理的果蝇AD模型中，我们操纵了人高亲和力铜进口orthopolysaccharide在果蝇中的表达，以探索铜离子在AD发展中的体内作用。我们发现，在表达Aβ的果蝇中，通过RNAi抑制Ctr 1C表达可显著减少果蝇脑中铜的积累，并改善神经退行性变，增强攀爬能力和延长寿命。有趣的是，Ctr 1C抑制导致脑裂解物中高分子量Aβ42形式显著增加，同时伴随着Ctr 1C RNAi果蝇中淀粉样蛋白-β降解蛋白酶（包括NEP 1 -3和IDE）表达随年龄增加而降低的趋势，以及Cu-Aβ相互作用诱导的氧化应激减少。在AD果蝇的神经系统中抑制另一个铜输入者Ctr 1B和过表达铜输出者DmATP 7也得到了类似的结果。这些结果表明，铜可能在AD的发生中起致病作用，因为在铜减少的环境或铜结合较少的环境中，Aβ寡聚体或聚集体的毒性较低。早期干预脑铜摄取可对Aβ病理改变产生重要影响。
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.
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影响因子：
3.7
作者：
Iijima K;Chiang HC;Hearn SA;Hakker I;Gatt A;Shenton C;Granger L;Leung A;Iijima-Ando K;Zhong Y
通讯作者：
Zhong Y
影响因子：
2.5
作者：
Bharathi;Indi, S. S.;Rao, K. S. J.
通讯作者：
Rao, K. S. J.
影响因子：
56.9
作者：
BUSH, AI;PETTINGELL, WH;TANZI, RE
通讯作者：
TANZI, RE
DOI：
10.1073/pnas.0230450100
发表时间：
2003-04-01
影响因子：
11.1
作者：
Farris, W;Mansourian, S;Guénette, S
通讯作者：
Guénette, S
影响因子：
3.5
作者：
Bleackley, Mark R.;MacGillivray, Ross T. A.
通讯作者：
MacGillivray, Ross T. A.