Enhanced Expression of the Voltage-Dependent Anion Channel 1 (VDAC1) in Alzheimer's Disease Transgenic Mice: An Insight into the Pathogenic Effects of Amyloid-β
Enhanced Expression of the Voltage-Dependent Anion Channel 1 (VDAC1) in Alzheimer's Disease Transgenic Mice: An Insight into the Pathogenic Effects of Amyloid-β
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DOI：
10.3233/jad-2010-100966
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发表时间：
2011-01-01
影响因子：
4
通讯作者：
Perez-Mediavilla, Alberto
中科院分区：
文献类型：
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作者：
Cuadrado-Tejedor, Mar;Vilarino, Marcos;Perez-Mediavilla, Alberto
线粒体电压依赖性阴离子通道1（VDAC 1）参与了可能与阿尔茨海默病（AD）神经病理学相关的凋亡蛋白的释放。通过蛋白质组学分析，随后的蛋白质印迹和免疫组织化学技术，我们发现VDAC 1在淀粉样变应性AD转基因小鼠模型的海马中过表达。VDAC 1在AD晚期患者的死后脑组织中也过表达。有趣的是，淀粉样蛋白-β（A β）可溶性寡聚体能够诱导人神经母细胞瘤细胞系中VDAC 1的上调，进一步支持A β水平与VDAC 1表达之间的相关性。在转基因小鼠的海马提取物中，观察到在对糖原合成酶激酶-3 β的磷酸化敏感的表位处磷酸化的VDAC 1水平显著增加，糖原合成酶激酶-3 β的活性也增加。在AD模型的线粒体样本中，与VDAC 1相互作用并影响其功能的己糖激酶I（HXKI）水平降低。由于磷酸-VDAC和降低的HXKI水平有利于VDAC 1构象状态更倾向于释放促凋亡因子，因此调节该通道的功能可能是对抗AD的有希望的治疗方法。
The mitochondrial voltage-dependent anion channel 1 (VDAC1) is involved in the release of apoptotic proteins with possible relevance in Alzheimer's disease (AD) neuropathology. Through proteomic analysis followed by Western blotting and immunohistochemical techniques, we have found that VDAC1 is overexpressed in the hippocampus from amyloidogenic AD transgenic mice models. VDAC1 was also overexpressed in postmortem brain tissue from AD patients at an advanced stage of the disease. Interestingly, amyloid-beta (A beta) soluble oligomers were able to induce upregulation of VDAC1 in a human neuroblastoma cell line, further supporting a correlation between A beta levels and VDAC1 expression. In hippocampal extracts from transgenic mice, a significant increase was observed in the levels of VDAC1 phosphorylated at an epitope that is susceptible to phosphorylation by glycogen synthase kinase-3 beta, whose activity was also increased. The levels of hexokinase I (HXKI), which interacts with VDAC1 and affects its function, were decreased in mitochondrial samples from AD models. Since phospho-VDAC and reduced HXKI levels favors a VDAC1 conformational state more prone to the release proapoptotic factors, regulation of the function of this channel may be a promising therapeutic approach to combat AD.