Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease.
Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease.
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DOI：
10.1016/j.cell.2010.08.014
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发表时间：
2010-09-17
期刊：
影响因子：
64.5
通讯作者：
Bush AI
中科院分区：
文献类型：
--
作者：
Duce JA;Tsatsanis A;Cater MA;James SA;Robb E;Wikhe K;Leong SL;Perez K;Johanssen T;Greenough MA;Cho HH;Galatis D;Moir RD;Masters CL;McLean C;Tanzi RE;Cappai R;Barnham KJ;Ciccotosto GD;Rogers JT;Bush AI
阿尔茨海默病（AD）是由促氧化剂神经元内Fe 2+升高以及淀粉样斑块内细胞外Zn 2+积累而复杂化的。我们发现AD β-淀粉样蛋白前体（APP）具有由一个保守的H-铁蛋白样活性位点介导的铁氧化酶活性，该活性位点可被Zn ~（2+）特异性抑制。与血浆铜蓝蛋白类似，APP催化氧化Fe 2+，将Fe 3+加载到转铁蛋白中，并与HEK 293 T细胞（缺乏血浆铜蓝蛋白）和人类皮质组织中的膜铁转运蛋白（ferroportin）发生主要相互作用。在HEK 293 T细胞和原代神经元中消融APP诱导显著的铁保留，而增加APP 695促进铁输出。与正常小鼠不同，APP−/−小鼠容易受到膳食铁暴露的影响，这会导致皮质神经元中的Fe 2+积累和氧化应激。除了铁积累，AD死后新皮层中APP铁氧化酶活性被内源性Zn 2+抑制，我们证明这可能来源于富含Zn 2+的淀粉样蛋白聚集体，并与Aβ负荷相关。皮质锌的异常交换可能与AD中淀粉样病变和神经元铁蓄积有关。
Alzheimer’s Disease (AD) is complicated by pro-oxidant intraneuronal Fe2+ elevation as well as extracellular Zn2+ accumulation within amyloid plaque. We found that the AD β-amyloid protein precursor (APP) possesses ferroxidase activity mediated by a conserved H-ferritin-like active site, which is inhibited specifically by Zn2+. Like ceruloplasmin, APP catalytically oxidizes Fe2+, loads Fe3+ into transferrin, and has a major interaction with ferroportin in HEK293T cells (that lack ceruloplasmin) and in human cortical tissue. Ablation of APP in HEK293T cells and primary neurons induces marked iron retention, whereas increasing APP695 promotes iron export. Unlike normal mice, APP−/− mice are vulnerable to dietary iron exposure, which causes Fe2+ accumulation and oxidative stress in cortical neurons. Paralleling iron accumulation, APP ferroxidase activity in AD post-mortem neocortex is inhibited by endogenous Zn2+, which we demonstrate can originate from Zn2+-laden amyloid aggregates and correlates with Aβ burden. Abnormal exchange of cortical zinc may link amyloid pathology with neuronal iron accumulation in AD.
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影响因子：
56.9
作者：
BUSH, AI;PETTINGELL, WH;TANZI, RE
通讯作者：
TANZI, RE
DOI：
10.1073/pnas.92.7.2539
发表时间：
1995-03-28
影响因子：
11.1
作者：
HARRIS, ZL;TAKAHASHI, Y;GITLIN, JD
通讯作者：
GITLIN, JD
影响因子：
1.7
作者：
GRAY, CW;PATEL, AJ
通讯作者：
PATEL, AJ
影响因子：
12.7
作者：
GRUNDKEIQBAL, I;FLEMING, J;JOSHI, JG
通讯作者：
JOSHI, JG
影响因子：
14.5
作者：
Chinnery, Patrick F.;Crompton, Douglas E.;Burn, John
通讯作者：
Burn, John