Alterations of zinc transporter proteins ZnT-1, ZnT-4 and ZnT-6 in preclinical Alzheimer's disease brain.
Alterations of zinc transporter proteins ZnT-1, ZnT-4 and ZnT-6 in preclinical Alzheimer's disease brain.
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DOI：
10.1111/j.1750-3639.2009.00283.x
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Lovell MA
中科院分区：
文献类型：
--
作者：
Lyubartseva G;Smith JL;Markesbery WR;Lovell MA
我们之前的研究表明，锌（Zn）转运蛋白ZnT-1、ZnT-4和ZnT-6在轻度认知障碍（MCI）、早期和晚期阿尔茨海默病（AD）受试者的易感脑区发生改变，并提示锌稳态的破坏可能在AD的发病机制中发挥作用。ZnT-1将锌从细胞质中输出到细胞外区室，ZnT-4将锌从细胞质中转运到溶酶体和核内体，ZnT-6在反式高尔基网络中隔离锌。阿尔茨海默病的临床前阶段（PCAD）已被描述，其中受试者没有明显的阿尔茨海默病临床表现，但在尸检时显示出明显的阿尔茨海默病病理。为了确定ZnT蛋白是否在PCAD中发生改变，我们使用Western blot分析和免疫组织化学方法检测了7名PCAD受试者和7名年龄匹配的正常对照（NC）受试者的海马/海马旁回（HPG）和小脑（CER）中的ZnT-1、ZnT-4和ZnT-6。我们的研究结果显示，PCAD组HPG中ZnT-1显著降低（P < 0.05）， PCAD CER中ZnT-4和ZnT-6显著升高，但PCAD CER较NC组显著降低。HPG代表性切片的共聚焦显微镜显示，改变的znt与MC-1免疫阳性的神经元相关，MC-1是一种单克隆抗体，可识别神经原纤维缠结形成早期的神经元。总之，我们的研究结果表明，锌转运蛋白的改变可能有助于pad受试者在出现临床症状之前观察到的病理变化。
Our previous studies demonstrate alterations of zinc (Zn) transporter proteins ZnT-1, ZnT-4, and ZnT-6 in vulnerable brain regions of subjects with mild cognitive impairment (MCI), early and late stage Alzheimer's disease (AD) and suggest that disruptions of Zn homeostasis may play a role in the pathogenesis of AD. ZnT-1 exports Zn from the cytosol to extracellular compartments, ZnT-4 transports Zn from the cytosol to lysosomes and endosomes, and ZnT-6 sequesters Zn in the trans-Golgi network. A preclinical stage of AD (PCAD) has been described in which subjects show no overt clinical manifestations of AD but demonstrate significant AD pathology at autopsy. To determine if alterations of ZnT proteins occur in PCAD we measured ZnT-1, ZnT-4, and ZnT-6 in the hippocampus/parahippocampal gyrus (HPG) and cerebellum (CER) of 7 PCAD subjects and 7 age matched normal control (NC) subjects using Western blot analysis and immunohistochemistry. Our results show a significant decrease (P < 0.05) of ZnT-1 in HPG of PCAD subjects, along with an increase of ZnT-4 in PCAD CER and ZnT-6 in PCAD HPG, but a significant decrease in PCAD CER compared to NC subjects. Confocal microscopy of representative sections of HPG shows altered ZnTs are associated with neurons immunopositive for MC-1, a monoclonal antibody that identifies neurons early in formation of neurofibrillary tangles. Overall, our results suggest that alterations in Zn transport proteins may contribute to the pathology observed in PCAD subjects before onset of clinical symptoms.
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影响因子：
3
作者：
Danscher, G;Jensen, KB;Ravid, R
通讯作者：
Ravid, R
影响因子：
3.7
作者：
Lovell, MA;Smith, JL;Markesbery, WR
通讯作者：
Markesbery, WR
影响因子：
56.9
作者：
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通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
4.4
作者：
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通讯作者：
Markesbery, WR