Voltage-Dependent Anion Channel and Neurodegeneration in Alzheimer's Disease

阿尔茨海默氏病的电压依赖性阴离子通道和神经变性

• 批准号: 8723663
• 负责人: P. Hemachandra Reddy
• 金额: $ 10.2万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2014-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723663
• 关键词: ATP Synthesis Pathway; Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Autopsy; Behavior; Biochemical; Biological Assay; Brain; Carrier Proteins; Cerebral cortex; Co-Immunoprecipitations; Cognitive; Defect; Digitonin; Disease Progression; Dissociation; Fractionation; Free Radicals; Functional disorder; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Goals; Guanosine Triphosphate Phosphohydrolases; Hydrogen Peroxide; Immunoblotting; Lead; Link; Lipid Peroxidation; Membrane; Membrane Proteins; Methods; Mitochondria; Morphology; Mus; Nerve Degeneration; Neuronal Dysfunction; Neurons; Outcome; Outer Mitochondrial Membrane; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Pathology; Patients; Permeability; Phosphorylation; Phosphotransferases; Physiological; Play; Production; Proteins; Relative (related person); Reporting; Research; Research Personnel; Respiration; Role; Staging; Structure; Synapses; Tissues; Transgenic Mice; Voltage-Dependent Anion Channel; Voltage-Dependent_Anion_Channel-1; Wild Type Mouse; base; brain tissue; cytochrome c oxidase; hexokinase; insight; mind control; mitochondrial dysfunction; protein metabolite; public health relevance; research study; tau Proteins; tau-1; therapy development

Project Summary The long-term goal of the proposed research is to understand the role of the voltage-dependent anion channel 1 (VDAC1) protein in Alzheimer's disease (AD) pathogenesis. Recent studies using postmortem AD brains, brain tissues from 6-, 12-, and 24-month-old A¿PP transgenic mice, and primary neurons from A¿PP and tau mice revealed that age, amyloid beta (A¿)-, and phosphorylated (phospho) tau-induced mitochondrial dysfunction and oxidative stress are key factors involved in neuronal dysfunction in AD pathogenesis. Researchers have reported that A¿ is associated with mitochondria localized at synapses and with synaptic damage and mitochondrial dysfunction. Preliminary research revealed that VDAC1, located in the outer membrane of mitochondria, was higher in the cortical tissues from AD patients and was also higher in the cerebral cortices of the 6-, 12-, and 24-month-old A¿PP mice. Research also revealed VDAC1 interacting with A¿ and phospho tau in the AD postmortem brains and in the cerebral cortices from APP, APPxPS1, and 3xAD.Tg mice. Mitochondrial functional analysis indicated increased free radicals, lipid peroxidation levels, and fission-linked GTPase activity, and decreased cytochrome oxidase and ATP levels in the APP transgenic mice. Preliminary research also indicated that A¿-induced activated glycogen synthase kinase 3¿ (GSK3¿) reduced hexokinases 1 and 2, and enhanced VDAC1 phosphorylation, leading to defects in mitochondrial structure/function. However, the links between A¿ and VDAC1 and between phospho tau and VDAC1 are unclear, and the relationship between GSK3¿ and VDAC1 phosphorylation to mitochondrial dysfunction are unclear. One hypothesis is that A¿ and phospho tau interact with VDAC1, which disrupts the transport of proteins/metabolites, resulting in defects in oxidative phosphorylation and in ATP synthesis. Another hypothesis is that a partial deficiency of VDAC1 maintains the mitochondrial pore activity in neurons producing A¿ and phospho tau, which in turn reduce mitochondrial dysfunction/synaptic damage in AD neurons. The proposed research objective is to determine the role of VDAC1 in mitochondrial dysfunction in relation to A¿ and phospho tau in AD pathogenesis. To this end, the proposed specific aims are: 1) to determine the physiological relevance of the interactions between VDAC1 and A¿, and between VDAC1 and phosphorylated tau in relation to VDAC1 phosphorylation and hexokinase reductions in AD neurons, 2) to determine whether reduced VDAC1 maintains mitochondrial pore activity and mitochondrial function in neurons producing A¿ and 3) phosphorylated tau. The outcomes of the experiments for these aims will provide new insights into the physiological relevance of increased levels of VDAC1 and its interactions with A¿ and phosphorylated tau in AD pathogenesis~ and will provide critical information that can be used to develop therapies for reducing A¿- and phosphorylated tau-induced mitochondrial damage and neuronal dysfunction in AD patients.

项目摘要 这项研究的长期目标是了解电压依赖性阴离子的作用 通道1（VDAC 1）蛋白在阿尔茨海默病（AD）发病机制中的作用。使用死后AD的最新研究 6个月、12个月和24个月大的A <$PP转基因小鼠的脑、脑组织和A <$PP的原代神经元 和tau蛋白小鼠发现，年龄、β淀粉样蛋白（A？）和磷酸化（磷酸化）tau蛋白诱导的线粒体 功能障碍和氧化应激是参与AD发病机制中神经元功能障碍的关键因素。 研究人员报告说，A？与位于突触处的线粒体有关， 损伤和线粒体功能障碍。初步研究表明，VDAC 1，位于外 线粒体膜，在AD患者的皮质组织中更高， 6个月、12个月和24个月大的A？PP小鼠的大脑皮质。研究还显示VDAC 1与 AD死后脑和APP、APPxPS 1和APPxPS 2的大脑皮层中的A？和磷酸化tau蛋白， 3xAD.Tg小鼠。线粒体功能分析表明，增加自由基，脂质过氧化水平， 在APP转基因小鼠中，分裂连接的GT3活性降低，细胞色素氧化酶和ATP水平降低。 初步研究还表明，A诱导的活化糖原合成酶激酶3（GSK 3）减少了 己糖激酶1和2，并增强VDAC 1磷酸化，导致线粒体 结构/功能。 然而，A？和VDAC 1之间以及磷酸化tau和VDAC 1之间的联系是 GSK 3和VDAC 1磷酸化与线粒体功能障碍之间的关系尚不清楚， 不清楚 一种假设是，A？和磷酸化tau与VDAC 1相互作用，破坏了 蛋白质/代谢物，导致氧化磷酸化和ATP合成缺陷。另一 一种假说是VDAC 1的部分缺乏维持了神经元中线粒体孔的活性， A？和磷酸化tau，这反过来又减少了AD神经元中的线粒体功能障碍/突触损伤。 拟议的研究目标是确定VDAC 1在线粒体功能障碍中的作用， 与AD发病机制中的A？和磷酸化tau蛋白的关系。 为此，建议的具体目标是： 确定VDAC 1和A？之间以及VDAC 1和A？之间相互作用的生理相关性。 与AD神经元中VDAC 1磷酸化和己糖激酶减少相关的磷酸化tau，2） 确定减少的VDAC 1是否维持神经元中的线粒体孔活性和线粒体功能 产生A？和3）磷酸化tau。这些目标的实验结果将提供新的 深入了解VDAC 1水平增加的生理相关性及其与A？和 磷酸化tau蛋白在AD发病机制中的作用，并将提供可用于开发 用于减少A β和磷酸化tau蛋白诱导的线粒体损伤和神经元功能障碍的疗法 AD患者。