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

描述（由申请人提供）：拟议研究的长期目标是了解电压依赖性阴离子通道1 （VDAC1）蛋白在阿尔茨海默病（AD）发病机制中的作用。最近对死后AD大脑、6、12、24月龄AbetaPP转基因小鼠脑组织以及AbetaPP和tau小鼠的原代神经元的研究表明，年龄、β淀粉样蛋白(Abeta)-和磷酸化（磷酸化）tau诱导的线粒体功能障碍和氧化应激是AD发病过程中神经元功能障碍的关键因素。研究人员已经报道了Abeta与位于突触的线粒体有关，并与突触损伤和线粒体功能障碍有关。初步研究发现，位于线粒体外膜的VDAC1在AD患者皮质组织中含量较高，在6、12、24月龄AbetaPP小鼠的大脑皮层中含量也较高。研究还发现，VDAC1在AD死后的大脑以及APP、APPxPS1和3xAD的大脑皮层中与β和磷酸化tau相互作用。Tg老鼠。线粒体功能分析显示，APP转基因小鼠的自由基、脂质过氧化水平和裂变相关GTPase活性增加，细胞色素氧化酶和ATP水平降低。前期研究还发现，abeta诱导的活化糖原合成酶激酶3 β (gsk3 β)降低己糖激酶1和己糖激酶2，增强VDAC1磷酸化，导致线粒体结构/功能缺陷。然而，Abeta和VDAC1之间以及磷酸化tau和VDAC1之间的联系尚不清楚，GSK3beta和VDAC1磷酸化与线粒体功能障碍之间的关系尚不清楚。一种假设是，β和磷酸化tau与VDAC1相互作用，破坏蛋白质/代谢物的运输，导致氧化磷酸化和ATP合成缺陷。另一种假设是VDAC1的部分缺失维持了产生Abeta和phospho tau的神经元的线粒体孔活性，从而减少了AD神经元的线粒体功能障碍/突触损伤。我们提出的研究目的是确定VDAC1在线粒体功能障碍中的作用，并与β和磷酸化tau蛋白在AD发病机制中的作用相关。为此，提出的具体目标是：1)确定VDAC1与Abeta之间相互作用的生理相关性，以及VDAC1与磷酸化的tau之间的相互作用与AD神经元中VDAC1磷酸化和hexokinase减少的关系；2)确定减少的VDAC1是否维持产生Abeta和磷酸化tau的神经元中的线粒体孔活性和线粒体功能。这些目的的实验结果将为VDAC1水平升高及其与Abeta和磷酸化tau的相互作用在AD发病机制中的生理相关性提供新的见解，并将提供关键信息，可用于开发减少Abeta和磷酸化tau诱导的AD患者线粒体损伤和神经元功能障碍的治疗方法。

DESCRIPTION (provided by applicant): 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 AbetaPP transgenic mice, and primary neurons from AbetaPP and tau mice revealed that age, amyloid beta (Abeta)-, and phosphorylated (phospho) tau-induced mitochondrial dysfunction and oxidative stress are key factors involved in neuronal dysfunction in AD pathogenesis. Researchers have reported that Abeta 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 AbetaPP mice. Research also revealed VDAC1 interacting with Abeta 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 Abeta-induced activated glycogen synthase kinase 3beta (GSK3beta) reduced hexokinases 1 and 2, and enhanced VDAC1 phosphorylation, leading to defects in mitochondrial structure/function. However, the links between Abeta and VDAC1 and between phospho tau and VDAC1 are unclear, and the relationship between GSK3beta and VDAC1 phosphorylation to mitochondrial dysfunction are unclear. One hypothesis is that Abeta 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 Abeta 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 Abeta 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 Abeta, 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 Abeta 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 Abeta and phosphorylated tau in AD pathogenesis~ and will provide critical information that can be used to develop therapies for reducing Abeta- and phosphorylated tau-induced mitochondrial damage and neuronal dysfunction in AD patients.