Reduced VDAC1 protects against Alzheimer's disease, mitochondria, and synaptic deficiencies.
Reduced VDAC1 protects against Alzheimer's disease, mitochondria, and synaptic deficiencies.
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DOI：
10.3233/jad-130761
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Reddy PH
中科院分区：
文献类型：
--
作者：
Manczak M;Sheiko T;Craigen WJ;Reddy PH
本研究的目的是阐明VDAC1对阿尔茨海默病(AD)相关基因、线粒体活性和突触活性的影响。最近对VDAC1基因敲除的研究表明，纯合子VDAC1基因敲除(VDAC1−/−)小鼠表现出学习和突触可塑性中断，而与野生型小鼠相比，VDAC1+/−小鼠在寿命、生育能力和生存能力方面表现出正常。然而，VDAC1降低对AD神经元线粒体/突触基因和线粒体功能的影响还不是很清楚。在本研究中，我们对VDAC1+/−和VDAC1+/+小鼠的线粒体/突触和AD相关基因和线粒体功能进行了研究。我们发现AD相关基因，包括AβPP，Tau，PS1，PS2和BACE1mRNA水平降低，线粒体融合基因Mfn1和Mfn2水平增加，分裂基因drp1和Fis1水平降低，线粒体通透性转换孔基因VDAC1，ANT和CypD水平降低。己糖激酶1和2在VDAC+/−小鼠中显著上调。突触基因突触素、突触素1和2、突触素1和2、神经颗粒素和PSD95在VDAC1+/−小鼠中也有上调。VDAC1+/−小鼠体内自由基生成和脂质过氧化水平降低，细胞色素氧化酶活性和三磷酸腺苷水平升高，提示VDAC1+/−小鼠线粒体功能增强。这些发现表明，降低VDAC1的表达，如我们在VDAC1+/−小鼠中发现的那样，可能有利于突触活动，可能改善功能，并可能保护AD相关基因的毒性。
The objective of this study was to elucidate the effect of VDAC1 on Alzheimer’s disease (AD)-related genes, mitochondrial activity, and synaptic viability. Recent knockout studies of VDAC1 revealed that homozygote VDAC1 knockout (VDAC1−/−) mice exhibited disrupted learning and synaptic plasticity, and in contrast, VDAC1+/− mice appeared normal in terms of lifespan, fertility, and viability relative to wild-type mice. However, the effects of reduced VDAC1 on mitochondrial/synaptic genes and mitochondrial function in AD-affected neurons are not well understood. In the present study, we characterized mitochondrial/synaptic and AD-related genes and mitochondrial function in VDAC1+/− mice and VDAC1+/+ mice. We found reduced mRNA levels in the AD-related genes, including AβPP, Tau, PS1, PS2, and BACE1; increased levels of the mitochondrial fusion genes Mfn1, Mfn2; reduced levels of the fission genes Drp1 and Fis1; and reduced levels of the mitochondrial permeability transition pore genes VDAC1, ANT, and CypD in VDAC1+/− mice relative to VDAC1+/+ mice. Hexokinase 1 and 2 were significantly upregulated in the VDAC+/− mice. The synaptic genes synaptophysin, synapsin 1 and 2, synaptobrevin 1 and 2, neurogranin, and PSD95 were also upregulated in the VDAC1+/− mice. Free radical production and lipid peroxidation levels were reduced in the VDAC1+/− mice, and cytochrome oxidase activity and ATP levels were elevated, indicating enhanced mitochondrial function in the VDAC1+/− mice. These findings suggest that reduced VDAC1 expression, such as that we found in the VDAC1+/− mice, may be beneficial to synaptic activity, may improve function, and may protect against toxicities of AD-related genes.