Alterations in zinc transporter protein-1 (ZnT-1) in the brain of subjects with mild cognitive impairment, early, and late-stage Alzheimer's disease
Alterations in zinc transporter protein-1 (ZnT-1) in the brain of subjects with mild cognitive impairment, early, and late-stage Alzheimer's disease
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DOI：
10.1007/bf03033884
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发表时间：
2005-01-01
影响因子：
3.7
通讯作者：
Markesbery, WR
中科院分区：
文献类型：
--
作者：
Lovell, MA;Smith, JL;Markesbery, WR
几项研究表明，阿尔茨海默病（AD）患者大脑中锌（Zn）含量增加。最近，突触锌和锌转运蛋白（ZnT）的改变与阿尔茨海默病动物模型中淀粉样斑块的积累有关。为了确定ZnT蛋白的改变是否存在于AD大脑中，我们测量了19名AD和14名年龄匹配的对照组中杏仁核（AMY）、海马/海马旁回（HPG）、颞上回和中颞回（SMTG）、下顶叶（IPL）和小脑（CER）中负责锌向细胞外空间输出的蛋白ZnT-1的水平。为了确定ZnT-1的改变是否发生在AD进展的早期，我们分析了5名轻度认知障碍患者（MCI）、5名早期AD患者（EAD）和4名年龄匹配的对照组的HPG、SMTG和CER中的蛋白质水平。Western blot和dot-blot分析显示，与年龄匹配的对照组相比，AD AMY、HPG和IPL中ZnT-1水平升高（p < 0.05）， AD SMTG中ZnT-1水平明显降低（p < 0.05）。我们还观察到，与对照组相比，EAD患者HPG中ZnT-1水平有统计学意义的升高。与晚期AD患者相比，与年龄匹配的对照组相比，MCI患者HPG中ZnT-1水平显著降低，MCI和EAD患者SMTG中ZnT-1水平显著升高。ZnT-1水平与AMY老年斑（SP）和神经原纤维缠结（NFT）计数的相关性分析显示，与SP计数呈显著（p < 0.05）正相关，与AMY神经原纤维缠结计数呈显著（p = 0.12）正相关。总的来说，我们的研究结果表明，在阿尔茨海默病进展早期，负责维持锌稳态的关键蛋白之一发生了改变，这表明锌平衡的改变可能参与了阿尔茨海默病神经元变性和淀粉样蛋白沉积的发病机制。
Several studies show increased levels of zinc (Zn) in the Alzheimer's disease (AD) brain. More recently, alterations in synaptic Zn and Zn transporter proteins (ZnT) have been implicated in the accumulation of amyloid plaques in an animal model of AD. To determine if alterations in ZnT proteins are present in AD brain, we measured levels of ZnT-1, the protein responsible for export of Zn to the extracellular space in the amygdala (AMY), hippocampus/parahippocampal gyrus (HPG), superior and middle temporal gyrus (SMTG), inferior parietal lobule (IPL), and cerebellum (CER) of 19 AD and 14 age-matched control subjects. To determine if alterations of ZnT-1 occur early in the progression of AD, we analyzed protein levels in the HPG, SMTG and CER of 5 subjects with mild cognitive impairment (MCI), 5 subjects with early AD (EAD) and 4 appropriately age-matched controls. Western blot and dot-blot analysis showed statistically significant (p < 0.05) elevations of ZnT-1 in AD AMY, HPG, and IPL and significantly depleted ZnT-1 in AD SMTG compared to age-matched control subjects. We also observed statistically significant elevations of ZnT-1 in the HPG of EAD subjects compared with controls. In contrast to late-stage AD subjects, ZnT-1 levels were significantly decreased in HPG of subjects with MCI and were significantly elevated in the SMTG of both MCI and EAD subjects compared with age-matched controls. Correlation analysis of ZnT-1 levels and senile plaque (SP) and neurofibrillary tangle (NFT) counts in the AMY and CA1 and subiculum of AD HPG showed a significant (p < 0.05) positive correlation with SP counts and a trend towards a significant (p = 0.12) positive correlation with NFT counts in AMY. Overall, our results show alterations in one of the key proteins responsible for maintenance of Zn homeostasis early in the progression of AD suggesting that alterations in Zn balance could be involved in the pathogenesis of neuron degeneration and amyloid deposition in AD.